Medical Marijuana and the "Entourage Effect" by Sanjay Gupta


By Dr. Sanjay Gupta, CNN chief medical correspondent Updated 1758 GMT (0158 HKT) March 11, 2014 In the early 1060's a young postdoctoral student stumbled onto something that puzzled him. After reading the literature on cannabis, he was surprised to see that while the active compound in morphine had been isolated from opium poppies 100 years before and cocaine isolated from coca leaves around the same time, the active component of marijuana was still unknown. This simple observation launched his life's work. That young Israeli researcher, Raphael Mechoulam, is now a heavily decorated scientist, recently nominated for the prestigious Rothschild Prize. More than 50 years ago, however, he had trouble starting his scientific journey. For starters, he needed cannabis to study and didn't know how to obtain it. Eventually, he obtained his research supply from friends in the police department. The young scientist was in a hurry, and didn't want to wait to cut through the red tape required by Israel's Health Ministry. Dr. Sanjay Gupta is a practicing neurosurgeon and CNN's chief medical correspondent. "Yes, I broke the law," he told me when I met with him in Tel Aviv last year, "but I apologized and explained what I was trying to do." It's a good thing the Israeli government didn't stall his progress, because Mechoulam was moving at breakneck speed. By 1963, he determined the structure of cannabidiol (CBD), an important component of marijuana. A year later, he became the first person to isolate delta-9 tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana. Over the ensuing decades, Mechoulam and his team continued to isolate numerous compounds from the cannabis plant. Their work also went a long way toward illuminating how the drug works in the brain. When Mechoulam's team identified the first known endogenous cannabinoid, a chemical actually made by the brain itself, he named it "anandamide." In the Sanskrit language, ananda means "supreme bliss," which gives us some insight into what Mechoulam thinks of cannabinoids overall. It was halfway through our long afternoon discussion that Mechoulam, now 83, pulled out a paper he had written in 1999, describing something known as "the entourage effect." Think of it like this: There are more than 480 natural components found within the cannabis plant, of which 66 have been classified as "cannabinoids." Those are chemicals unique to the plant, including delta-9-tetrahydrocannabinol and cannabidiols. There are, however, many more, including: -- Cannabigerols (CBG); -- Cannabichromenes (CBC); -- other Cannabidiols (CBD); -- other Tetrahydrocannabinols (THC); -- Cannabinol (CBN) and cannabinodiol (CBDL); -- other cannabinoids (such as cannabicyclol (CBL), cannabielsoin (CBE), cannabitriol (CBT) and other miscellaneous types). Other constituents of the cannabis plant are: nitrogenous compounds (27 known), amino acids (18), proteins (3), glycoproteins (6), enzymes (2), sugars and related compounds (34), hydrocarbons (50), simple alcohols (7), aldehydes (13), ketones (13), simple acids (21), fatty acids (22), simple esters (12), lactones (1), steroids (11), terpenes (120), non-cannabinoid phenols (25), flavonoids (21), vitamins (1), pigments (2), and other elements (9). Minister's daughter: Cannabis "a gift from God" Here is the important point. Mechoulam, along with many others, said he believes all these components of the cannabis plant likely exert some therapeutic effect, more than any single compound alone. While science has not yet shown the exact role or mechanism for all these various compounds, evidence is mounting that these compounds work better together than in isolation: That is the "entourage effect." Take the case of Marinol, which is pure, synthetic THC. When the drug became available in the mid-1980s, scientists thought it would have the same effect as the whole cannabis plant. But it soon became clear that most patients preferred using the whole plant to taking Marinol. Researchers began to realize that other components, such as CBD, might have a larger role than previously realized. To better understand the concept of the entourage effect, I traveled to the secret labs of GW Pharmaceuticals, outside London. In developing Sativex, a cannabis-based drug to treat multiple sclerosis, the company's chairman, Dr. Geoffrey Guy, told me the company ran into some of the same obstacles that Marinol faced. More than a decade of experiments revealed that a whole plant extract, bred to contain roughly the same amounts of THC and CBD in addition to the other components in the plant, was more effective in reducing the pain and spasms of MS than a medication made of a single compound. It could be that multiple individual compounds play a role, or it could be due to their interaction in the body; it could also be combination of both, Guy said. Now, maybe this all sounds obvious. After all, eating real fruits, vegetables and other plants provides better nutrition than just taking vitamin pills with one nutrient or mineral in each. Science is showing us that we can likely say the same about cannabis. As we move forward with creating medicines, like Charlotte's Web, for the patients who can benefit from cannabis -- this is an important point to keep in mind. Unlike other drugs that may work well as single compounds, synthesized in a lab, cannabis may offer its most profound benefit as a whole plant, if we let the entourage effect flower, as Mechoulam suggested more than a decade ago. http://edition.cnn.com/2014/03/11/health/gupta-marijuana-entourage/




Botany of Desire - 4 plants, including Cannabis


They are four of the most ordinary plants. We've always had this idea that we are in charge, but what if, in fact, they have been modeling us? We don't give enough recognition to plants. They have been laboring on us, and they've been utilizing us for their own goals. There are four plants that have walked the road to accomplishment by fulfilling human ambitions. The tulip, by satisfying our longing for a certain kind of attractiveness, has gotten us to take it from its basis in Central Asia and distribute it around the world.

Marijuana, by satisfying our ambition to change awareness, has gotten us to risk our lives and freedom, in order to produce more of it. The potato, by fulfilling our desire for mastery, the control over surrounding, so that we can nourish ourselves has gotten itself out of South America and extended its range far beyond where it was long time ago. And the apple, by satisfying our appetite for sweetness, begins in the woods of Kazakhstan and is now the worldwide fruit. These are great champions in the game of domestication.

The bee believes it's getting the best of the deal with the blooming apple. It's getting in, it's taking the nectar and has no sense that it's picked up the pollen and is transferring it to another location. For the bee to assume that it's in charge of this friendship is really just a lack of success of bee's insight. We have the same failure of imagination. We are too working for the potatoes in some sense. We are planting them, we are giving them a habitat, and in the same time we think we're calling the shots.

Wouldn't it be appealing to look at our connection to domesticated plants from the plants' perspective? Of course, plants don't have awareness or goals, but by using our consciousness we can put ourselves in their roots to see things from their angle. When we do that, nature unexpectedly looks very different. We become aware that we're in the nature's web, not outside of it. These plants are reflectors in which we can see ourselves in a different way.




Medical Cannabis and its Effect on Human Health - A cannabis documentary





Dept of Health and Human Services USA - Medical Marijuana


People have used marijuana, also called cannabis, for a variety of health conditions for at least 3,000 years. The U.S. Food and Drug Administration (FDA) hasn’t found that marijuana is safe or effective for treating any health problems. However, some states and the District of Columbia allow its use for certain health purposes. States have legalized medical marijuana because of decisions made by voters or legislators—not because of scientific evidence of its benefits and risks.

It’s challenging to study the health effects of marijuana because of legal restrictions and variability in the concentration of the plant’s psychoactive chemicals. However, recently the Federal Government eased some research restrictions and also began providing researchers with more strains of marijuana. Currently, the quality of health research on marijuana and its components (other than two FDA-approved medications) varies widely by disease.

In January 2017, the National Academies of Sciences, Engineering, and Medicine published a report (link is external) on the health effects of marijuana and products derived from it. The report summarizes the current evidence on both therapeutic effects and harmful effects, recommends that research be done to develop a comprehensive understanding of the health effects of marijuana, and recommends that steps be taken to overcome regulatory barriers that may make it difficult to do research on marijuana’s health effects.

The National Institute on Drug Abuse (NIDA) has more information on many aspects of marijuana, including how likely people are to abuse it and how chemicals in marijuana affect our brain and body.

This page primarily focuses on the use of the marijuana plant, usually by smoking, for health-related purposes. The FDA has approved two prescription drugs, dronabinol and nabilone, based on a component of marijuana. These medications may be helpful for treating the symptoms associated with cancer or for the side effects of cancer therapies. In Europe, the United Kingdom, and Canada, a mouth and throat spray called nabiximols, which is derived directly from the marijuana plant and contains two of the plant’s components, has been licensed and approved for the relief of pain and spasticity associated with multiple sclerosis and as an addition to pain treatment for cancer patients. Studies of nabiximols are in progress in the United States.

https://nccih.nih.gov/health/marijuana




Scientists Want the Smoke to Clear on Med MJ Research


As U.S. policy lurches along, researchers say easing DEA rules could lead to big advances

Editor’s Note (8/11/16): The U.S. Drug Enforcement Administration is announcing today that it will keep marijuana illegal for any purpose (classified as a Schedule I substance under the Controlled Substances Act), but the government will soften rules for marijuana research to make it easier to grow the plant for scientific study. The following article was originally published in the lead-up to this decision.

For neuroscientist Chuanhai Cao, the problem with the U.S. Drug Enforcement Administration’s classification of marijuana as a Schedule I drug can be summed up in two words: dead mice.

Cao, a researcher at the University of South Florida’s Byrd Alzheimer’s Institute, uses transgenic mice to study the effect of the marijuana component tetrahydrocannabinol (THC) on amyloid beta, the protein that forms the plaque found in the brains of Alzheimer’s patients. Timing is critical in his work—the mice, which are difficult to breed, have to be a specific age at the time of an experiment. One Cao project, designed for 12-month-old mice, was delayed three months while the Drug Enforcement Administration (DEA) processed the complicated paperwork that all marijuana researchers must submit under the current system. Some of the mice died while Cao waited for the approvals he needed to acquire the THC for the experiment; he ended up with too few animals that were all too old to generate useful data. “It was a disaster,” he says.

The sting of that calamity, and of similar DEA-related snafus in labs around the country, could be soothed somewhat this summer if the agency decides in July to remove marijuana from its Schedule I list of controlled substances, which includes heroin, and reclassify it. “I’d be very excited to see that,” says Cao, who wants marijuana moved to Schedule III, which includes drugs like Tylenol with codeine and involves a less arduous DEA approval process.

Sachin Patel, an associate professor of psychiatry at Vanderbilt University School of Medicine who studies “the role of endogenous cannabinoids as mediators of stress resiliency,” would be satisfied with a more modest change. “Rescheduling cannabis as Schedule II will allow the research to get done that needs to be done to determine if this is going to be a good medicine, and for what,” says Patel, who has been researching cannabis for 15 years. Schedule II lists drugs deemed to have a high potential for abuse, including oxycodone or Percocet.

Marijuana is widely recognized as an often-effective treatment for a variety of common conditions. Even though it remains illegal at the federal level, 23 states and the District of Columbia have legalized its use for chronic pain, nausea, glaucoma, migraine and more. But researchers like Patel and Cao believe cannabis has even greater potential in the treatment of major disorders including Alzheimer’s, cancer, epilepsy, post-traumatic stress disorder and autoimmune diseases. They have committed their careers to it and, despite the onerous restrictions and endless hassles—Patel once waited six months for a DEA green-light—they have made real progress and routinely published their findings. A decision by the DEA to reschedule, although it will not completely remove the onus of illegality or the burden on scientists, could launch a new era in marijuana research.

“It’s not that we don’t have a lot of information,” says Lester Grinspoon, who has been researching and writing about marijuana since the 1960s and would prefer the DEA to delist it altogether. “If you go to PubMed you’ll find that there are 23,000 papers published on cannabis. But [with rescheduling] we can open it up to large, double-blind clinical studies.” Grinspoon, 87, an associate professor emeritus of psychiatry at Harvard Medical School, sees similarities to the history of another drug. “We didn’t have any large double-blind studies of penicillin until the mid-60s,” he says, “so it was all anecdotal evidence. But it came across as a wonder drug. And it was.”

Easing DEA restrictions could accelerate the pace and amount of research going on, including the fundamental in vitro work that people like Cao do. (In a 2014 paper published in the Journal of Alzheimer’s Disease, for example, he reported that extremely low concentrations of THC could reduce the production of amyloid beta in a cellular model of Alzheimer’s.) It could also draw more scientists into the field, open up more avenues of research and make it less difficult to attract funding. And, as Patel points out, whereas rigorous, placebo-controlled clinical trials might confirm popular notions about marijuana’s effectiveness for things like pain and nausea, they could possibly disprove them if the anecdotal evidence is trumped by science. Without such testing, he says, “We don’t really know.” A more likely outcome, Grinspoon adds, is that a new wave of research unencumbered by Schedule I status will prove that marijuana is the versatile, nontoxic, inexpensive medication he has found it to be.

Of course, the DEA is not the only obstacle. Research must also follow federal regulations that are separate from the DEA’s controlled substance schedules and require the marijuana used in studies where human subjects ingest it to come from a single source: the National Center for Natural Products Research at the University of Mississippi. And a 2015 analysis done at Arizona State University found that between 2008 and 2014, of the $1.4 billion the National Institutes of Health spent on marijuana research, just $297 million was spent on potential medical uses; the rest, $1.1 billion, went for abuse and addiction studies.

Still, Grinspoon thinks DEA rescheduling could go a long way toward changing the way the medical establishment views marijuana and the value of studying it. “Miseducation about cannabis over the last 50 years has been so thorough that it’s going to take time,” he says. “But this will knock down one of those obstacles.” One possible result: “Medical schools will start to recognize that they have to teach about cannabis as an important new medicine. Of course, it’s been around for 10,000 years, but new in the sense of coming to Western medicine.”

Whether or not he gets the Schedule III decision he is hoping for, Cao will continue on the path he has followed for nearly 10 years. For him, THC research is a long-term proposition and a personal quest. “We are trying to find therapies for Alzheimer’s patients,” he says, “and my mom is an Alzheimer’s patient.” If there is any possibility that marijuana could provide an effective treatment, he’ll pursue it, no matter what regulatory hurdles he has to clear.

https://www.scientificamerican.com/article/scientists-want-the-smoke-to-clear-on-medical-marijuana-research/




Center for Medicinal Cannabis Research


Please go to this link to see the newst research completed at the Center for Medicinal Cannabis Research http://www.cmcr.ucsd.edu/index.php





Current CBD Research

What is THC?


Most people know that THC, or tetrahydrocannabinol, is the chemical compound in cannabis responsible for a euphoric high. But what more is there to know about cannabis' primary psychoactive component? Whether the question comes as a newbie to the cannabis world or an experienced consumer who would like to know a bit more about the most famous of cannabinoids, THC has likely been synonymous with cannabis in your mind for as long as you've known about the plant. Let's dig a little deeper into what THC is and how it works. THC is a Cannabinoid, but What's a Cannabinoid? The first step to understanding THC is to understand cannabinoids. Cannabinoids are chemical compounds found in the cannabis plant that interact with receptors in the brain and body to create various effects. There exist dozens, and potentially more than 100, cannabinoids in the cannabis plant, but THC is most widely known among these due to its abundance and psychoactive attributes. The isolation of THC came from an Israeli chemist by the name of Raphael Mechoulam. In 1964, Mechoulam isolated and synthesized THC from Lebanese hashish, marking the beginning of cannabis research that would lead to the discovery of many other cannabinoids, cannabinoid receptors throughout the body, and "endocannabinoids" - the THC-like compounds our body naturally produces to maintain stability and health. Why does cannabis produce cannabinoids? Cannabinoids are known as secondary metabolites, which means they are chemicals the plant produces that have no primary role on the plant's development. However, the leading hypothesis is that secondary metabolites act as an immune system for the plant, fending off predators, parasites, and pests. Because humans (and many other animals) have receptor systems that THC binds to, we can also reap the benefits of cannabinoids for both health and enjoyment. This system, called the endocannabinoid system (or ECS), is a group of specialized signaling chemicals (think "keys"), their receptors (think "locks"), and the metabolic enzymes that produce and break them down. These endocannabinoid chemical signals act on some of the same brain and immune cell receptors (CB1 and CB2) that plant cannabinoids like cannabidiol (CBD) and ?9-tetrahydrocannabinol (THC) act on. How Does THC Produce Its Effects and Get Us High? Simply put, THC works by binding to cannabinoid receptors concentrated in the brain and central nervous system to produce psychoactive effects. But does that mean our bodies evolved for cannabis? Well, not quite. Before envisioning a symbiotic relationship between cannabis and humans, it's important to be introduced to "endogenous cannabinoids" such as anandamide and 2AG - the human body's naturally occurring cannabinoids. You may be familiar with anandamide if you're, say, a runner and have experienced the wave of euphoria after a successful jog, commonly known as "runner's high." The bottom line? Our bodies evolved to interact with natural cannabinoids such as anandamide, but this same system is responsible for the effects experienced from THC and other cannabinoids. What to Expect from a THC High THC has a wide range of short-term effects which may or may not be experienced depending on the individual. For example, while some may find that THC elicits strong feelings of calm and peace, others may notice an increase in their anxiety levels. The difference can be as simple as one's own body chemistry, but certain strains and varying concentrations of THC can also create different outcomes in how one feels. If one cannabis strain elicits unpleasant feelings, another may be just the right medley to induce a very enjoyable sensation. Consider consulting a thorough strain database to find what's right for you, and as always, it's wise to "start low and go slow" - consume a little at a time and then wait to see how you feel. Remember, a cannabis high can last for a few hours, but it will wear off. Some short-term effects of THC include: Elation Relaxation Sedation Pain relief Memory impairment Energy Hunger Drowsiness Increased heart rate Dry mouth Red eyes Slowed perception of time Laughter Dizziness "Couch-lock," or feeling heavy Anxiety/paranoia https://www.leafly.com/news/cannabis-101/what-is-tetrahydrocannabinol




Raphael Mechoulam on Components of Cannabis


The emerging significance of cannabis components other than THC was again a prominent theme when the International Association of Cannabis as Medicine met in Cologne in early October, 2007. The IACM was founded in 1997 by Franjo Grotenhermen, MD (as the German ACM); it is a smaller organization than the ICRS and its focus is more clinical, less pharmacological. Raphael Mechoulam of the Hebrew University, Jerusalem, Faculty of Medicine gave a talk on cannabidiol on the occasion, he noted, of his 45th year of involvement in the field. In October, 1962 Mechoulam had just gotten his PhD in chemistry and was looking for a research project that might lead to tenure at the Weizmann Institute. He chose to analyze the components of cannabis, he said, thinking “it’s a minor project; it will be finished off in six months’ Hashish of Lebanese origin was obtained from the police and a dozen constituents ere then identified by two types of chromatography. (Some cannabis constituents had been identified previously, including CBD, which Roger Adams of the University of Illinois isolated in the early 1940s.) Mechoulam and his co-workers elucidated the exact chemical structure of CBD in 1963 and of THC the following year. It was generally assumed for almost two decades that the cannabinoids exerted effects not by binding to a specific receptor but “nonspecifically” by altering the lipid structure of cellular membranes. Mechoulam established that the action was specific by purifying THC and showing that only the natural version of the molecule —and not its synthetic mirror image— was exerting the effect. In 1988 Alynn Howlett found that THC was indeed activating a receptor. It was dubbed “CB1” and was found in those areas of the brain involved in movement, stress, cognitive function — “everywhere it would be expected,” said Mechoulam, given what was known about the effects of cannabis on people. “A receptor doesn’t exist in the brain just because there’s a plant out there,” Mechoulam reasoned, “chances are there are endogenous compounds that will act on these receptors —so we went after them.” Whereas others were looking for peptides, Mechoulam figured the CB1 receptor would be activated by a lipid. Sophisticated analytical techniques and brilliant, dedicated lab workers (“They should not be married so they can work 24 hours a day, seven days a week”) enabled Mechoulam to isolate a cannabinoid produced by the body itself —arachidonoyl-ethanolamide or AEA, which his colleague William Devane dubbed “anandamide,” incorporating the Sanskrit word for “bliss.” Mechoulam’s lab isolated a second endogenous compound, arachidonoyl glyceride, or 2-AG, which is more abundant in the body but less potent than anandamide. Although their structures are different, AEA, 2-AG and THC have similar pharmacological effects. The receptors to which they bind weave in and out of the cell membrane and are coupled to a protein that triggers events within the cell leading to slowed release of neurotransmitters. (Think of a tiny doorknob twisting on the outside of a frenzied beehive and starting a sequence of events on the inside that results in fewer bees departing the hive.) Because the cannabinoids affect the intensity with which other neurotransmitters are firing, they modulate numerous systems within the body. Mechoulam said, “There is almost no physiological system that has been looked into in which endocannabinoids don’t play a certain part.” CBD binds to a second cannabinoid receptor —CB2—originally found in spleen cells by S. Munro of Cambridge University in 1993 and subsequently found in the stomach, liver, heart, kidney, lymph and immune cells, bones, endocrine glands, and throughout the peripheral nervous system. In his IACM talk Mechoulam reviewed research in recent years that has shed light on aspects of CBD’s mechanism of action. Its lipid-solubility enables it to get into places in the brain that conventional neurotransmitters cannot reach. It is a potent anti-oxidative agent. It turns out to be an antagonistto a recently discovered receptor called GPR-55 to which THC and 2-AG bind as agonists. It blocks the uptake of adenosine, an inhibitory neurotransmitter that may promote sleep. It blocks the formation of various cytokines (signaling compounds not released by nerves or glands) under certain circumstancs. It activates the serotonin receptors. No wonder, then, that CBD plays a role in many clinical conditions. Mechoulam described an experiment led by Paul Consroe and colleagues in Brazil in which BD was tested as a treatment for intractable epilepsy. Patients stayed on the anticonvulsants they had been on (which hadn’t eliminated their seizures) and added 200mg/day of CBD or a placebo. Of the seven patients getting CBD over the course of several months, only one showed no improvement; three became seizure-free; one experienced only one or two seizures, Mechoulam recalled; and two experienced reduced severity and occurrence of seizures. So it seemed a very promising approach,” said Mechoulam, “but unfortunately, nothing has been done ever since. To the best of my knowledge, nobody has done any work on cannabidiol in the clinic on epilepsy, and I just wonder why.” A colleague of Mechoulam’s, Marc Feldman at Imperial College, London, tested CBD on mice who had a version of rheumatoid arthritis and found that it reduced inflammation by almost 50% at the right dose —5mg/kg of body weight. But this “beautiful antiinflammatory reaction was lost if we went up to, say, 25 mg/kg,” Mechoulam said. Drug developers must bear in mind and cope with the fact that cannabinoids have a finite “therapeutic window” and may be ineffective at low and high doses. Mechoulam has been testing CBD on mice bred to have a version of type-1 diabetes that manifests around age 14 weeks. He and his co-workers treated these mice with CBD for their first 6-7 weeks of life, then tested them 6-7 weeks later and found that only 30% had developed diabetes (compared to 90-100% given placebo). In a follow-up experiment the mice weren’t given a course of CBD until age 14 weeks, when they were developing diabetes. They were then tested at age 24 weeks, and again only 30% of the treated mice were found to have diabetes. In other words, CBD did not just prevent onset but blocked development of diabetes. Examination of the insulin-producing islets showed that only 8% were intact in the untreated diabetic mice, whereas 77% were intact in the mice treated with CBD. “I believe that here we have something very promising,” Mechoulam said. “We plan to have a clinical trial starting next week treating patients, and hopefully at the next meeting I will tell you that all of them are cured.” Cardiologists working with mice at Hebrew University have found that CBD treatment at the time of a heart attack can reduce infarct size by about 66%. “So now they’re pushing me, ‘let’s have more CBD,’” Mechoulam said. “We should try it with humans in a few years.” He went on: “What about sleep? I’m jumping from thing to thing to show you that CBD does quite a lot of things and I’m not sure that all of them are according to the same mechanism.” Mechoulam was part of a group led by Eric Murillo-Rodriguez that administered CBD to rats and determined that while THC caused sleepiness, CBD increased wakefulness and significantly decreased REM sleep. According to Mechoulam, “When one says ‘cannabis causes sleep,’ one should think really of two compounds, one that causes sleep and one that causes awakening.” The anti-nausea and memory extinction effects of CBD “seem to be closely related,” Mechoulam said. He described the problem of anticipatory nausea, for which no good drugs are available. (The effects of chemotherapy can be so nauseating that patients start vomiting when they see the doctor or nurse who is going to administer the treatment.) Linda Parker at the University of Guelph conditioned shrews to start vomiting by administering lithium fluoride at a certain location. When the shrews were subsequently placed in that location they began vomiting. But if given CBD, they could be moved to the dreaded location without vomiting. [THC is anti-emetic, too; the advantage of CBD in this instance may be legal rather than medical.] “The conditioned-wretching reaction was completely abolished,” Mechoulam declared. “Can we abolish other kinds of conditioning?”He described an experiment in which rats had a choice of two paths, one leading to cocaine. Rats like cocaine (and amphetamine) and will learn to choose the path leading to it. But if injected with CBD, they no longer show a preference for cocaine! Mechoulam characterized post-traumatic stress disorder, certain phobias and forms of chronic pain as “human situations which are conditioned” and might be amenable to treatment with CBD. “I know that many patients with PTSD take cannabis, self administered,” Mechoulam said. He has been trying to interest the Israeli Ministry of Health in testing CBD and THC at various ratios to treat PTSD. by Fred Garner https://www.projectcbd.org/sites/projectcbd/files/downloads/mechoulam-iacm-07.pdf




What is CBD?


Cannabidiol—CBD—is a cannabis compound that has significant medical benefits, but does not make people feel “stoned” and can actually counteract the psychoactivity of THC. The fact that CBD-rich cannabis is non-psychoactive or less psychoactive than THC-dominant strains makes it an appealing option for patients looking for relief from inflammation, pain, anxiety, psychosis, seizures, spasms, and other conditions without disconcerting feelings of lethargy or dysphoria.

Scientific and clinical research—much of it sponsored by the US government—underscores CBD’s potential as a treatment for a wide range of conditions, including arthritis, diabetes, alcoholism, MS, chronic pain, schizophrenia, PTSD, depression, antibiotic-resistant infections, epilepsy, and other neurological disorders. CBD has demonstrable neuroprotective and neurogenic effects, and its anti-cancer properties are currently being investigated at several academic research centers in the United States and elsewhere. Further evidence suggests that CBD is safe even at high doses.

Project CBD responds to inquiries from all over the world. Almost everyone wants to know where to get CBD-rich products and how to use them for maximum benefit. After decades in which only high-THC cannabis was available in North America and beyond, CBD-rich strains and products are now available to medical users.

“CBD-rich” versus “CBD dominant:” By “CBD-rich,” we mean a cannabis strain or product that has equal amounts of CBD and THC, or more CBD than THC (usually at least 4 percent CBD by dry weight.). By “CBD-dominant,” we mean strains or products that are CBD-rich but have very little THC content.

https://www.projectcbd.org/about/what-cbd




CBD Users Manual


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. 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. 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. 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. 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. 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. 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. 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. 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. https://www.projectcbd.org/guidance/cbd-users-manual




Science Seeks to Unlock Marijuana Secrets


As the once-vilified drug becomes more accepted, researchers around the world are trying to understand how it works and how it might fight disease.There’s nothing new about cannabis, of course. It’s been around humankind pretty much forever.In Siberia charred seeds have been found inside burial mounds dating back to 3000 B.C. The Chinese were using cannabis as a medicine thousands of years ago. Marijuana is deeply American too—as American as George Washington, who grew hemp at Mount Vernon. For most of the country’s history, cannabis was legal, commonly found in tinctures and extracts. Then came Reefer Madness. Marijuana, the Assassin of Youth. The Killer Weed. The Gateway Drug. For nearly 70 years the plant went into hiding, and medical research largely stopped. In 1970 the federal government made it even harder to study marijuana, classifying it as a Schedule I drug—a dangerous substance with no valid medical purpose and a high potential for abuse, in the same category as heroin. In America most people expanding knowledge about cannabis were by definition criminals.But now, as more and more people are turning to the drug to treat ailments, the science of cannabis is experiencing a rebirth. We’re finding surprises, and possibly miracles, concealed inside this once forbidden plant. Although marijuana is still classified as a Schedule I drug, Vivek Murthy, the U.S. surgeon general, recently expressed interest in what science will learn about marijuana, noting that preliminary data show that “for certain medical conditions and symptoms” it can be “helpful.”states and the District of Columbia cannabis is legal for some medical uses, and a majority of Americans favor legalization for recreational use. Other countries are rethinking their relationship to pot too. Uruguay has voted to legalize it. Portugal has decriminalized it. Israel, Canada, and the Netherlands have medical marijuana programs, and in recent years numerous countries have liberalized possession laws.Ganja is simply around us more, its unmistakable but increasingly unremarkable smell hanging in the air. Yes, smoking it may lead to temporary laughing sickness, intense shoe-gazing, amnesia about what happened two seconds ago, and a ravenous yearning for Cheez Doodles. Though there’s never been a death reported from an overdose, marijuana—especially today’s stout iterations—is also a powerful and in some circumstances harmful drug. Hoping to help their sick children, three sets of parents turn to medical marijuana as a last resort.Still, for many, cannabis has become a tonic to dull pain, aid sleep, stimulate appetite, buffer life’s thumps and shocks. Pot’s champions say it peels back layers of stress. It’s also thought to be useful as, among other things, an analgesic, an antiemetic, a bronchodilator, and an anti-inflammatory. It’s even been found to help cure a bad case of the hiccups. Compounds in the plant, some scientists contend, may help the body regulate vital functions—such as protecting the brain against trauma, boosting the immune system, and aiding in “memory extinction” after catastrophic events.In the apparent rush to accept weed into the mainstream, to tax and regulate it, to legitimize and commodify it, important questions arise. What’s going on inside this plant? How does marijuana really affect our bodies and our brains? What might the chemicals in it tell us about how our neurological systems function? Could those chemicals lead us to beneficial new pharmaceuticals?If cannabis has something to tell us, what’s it saying? The Chemist:Treasure Trove Even into the middle of the 20th century, science still didn’t understand the first thing about marijuana. What was inside it and how it worked remained a mystery. Because of its illegality and tainted image, few serious scientists wanted to besmirch their reputations by studying it.Then one day in 1963 a young organic chemist in Israel named Raphael Mechoulam, working at the Weizmann Institute of Science outside Tel Aviv, decided to peer into the plant’s chemical composition. It struck him as odd that even though morphine had been teased from opium in 1805 and cocaine from coca leaves in 1855, scientists had no idea what the principal psychoactive ingredient was in marijuana. “It was just a plant,” says Mechoulam, now 84. “It was a mess, a mélange of unidentified compounds.”So Mechoulam called the Israeli national police and scored five kilos of confiscated Lebanese hashish. He and his research group isolated—and in some cases also synthesized—an array of substances, which he injected separately into rhesus monkeys. Only one had any observable effect. “Normally the rhesus monkey is quite an aggressive individual,” he says. But when injected with this compound, the monkeys became emphatically calm. “Sedated, I would say,” he recalls with a chuckle. Further testing found what the world now knows: This compound is the plant’s principal active ingredient, its mind-altering essence—the stuff that makes you high. Mechoulam, along with a colleague, had discovered tetrahydrocannabinol (THC). He and his team also elucidated the chemical structure of cannabidiol (CBD), another key ingredient in marijuana, one that has many potential medical uses but no psychoactive effect on humans.For these breakthroughs and many others, Mechoulam is widely known as the patriarch of cannabis science. Born in Bulgaria, he is a decorous man with wispy white hair and watery eyes who wears natty tweeds, silk scarves, and crisp dress slacks. He’s a respected member of the Israel Academy of Sciences and Humanities and an emeritus professor at Hebrew University’s Hadassah Medical School, where he still runs a lab. The author of more than 400 scientific papers and the holder of about 25 patents, this kindly grandfather has spent a lifetime studying cannabis, which he calls a “medicinal treasure trove waiting to be discovered.” His work has spawned a subculture of cannabis research around the globe. Though he says he’s never smoked the stuff, he’s a celebrity in the pot world and receives prodigious amounts of fan mail.“It’s all your fault,” I say to him when we meet in his book-lined, award-crammed office to discuss the explosion of interest in the science of marijuana.“Mea culpa!” he replies with a smile.Israel has one of the world’s most advanced medical marijuana programs. Mechoulam played an active role in setting it up, and he’s proud of the results. More than 20,000 patients have a license to use cannabis to treat such conditions as glaucoma, Crohn’s disease, inflammation, appetite loss, Tourette’s syndrome, and asthma.Despite that, he’s not particularly in favor of legalizing cannabis for recreational use. He doesn’t think anyone should go to jail for possessing it, but he insists that marijuana is “not an innocuous substance”—especially for young people. He cites studies showing that the prolonged use of high-THC strains of marijuana can change the way the developing brain grows. He notes that in some people cannabis can provoke serious and debilitating anxiety attacks. And he points to studies that suggest cannabis may trigger the onset of schizophrenia among those who have a genetic predisposition to the disease.If he had his way, what Mechoulam regards as the often irresponsible silliness of recreational pot culture would give way to an earnest and enthusiastic embrace of cannabis—but only as a medical substance to be strictly regulated and relentlessly researched. “Right now,” he complains, “people don’t know what they’re getting. For it to work in the medical world, it has to be quantitative. If you can’t count it, it’s not science.”In 1992 Mechoulam’s quest for quantification led him from the plant itself to the inner recesses of the human brain. That year he and several colleagues made an extraordinary discovery. They isolated the chemical made by the human body that binds to the same receptor in the brain that THC does. Mechoulam named it anandamide—from the Sanskrit for “supreme joy.” (When asked why he didn’t give it a Hebrew name, he replies, “Because in Hebrew there are not so many words for happiness. Jews don’t like being happy.”) Since then several other so-called endocannabinoids and their receptors have been discovered. Scientists have come to recognize that endocannabinoids interact with a specific neurological network—much the way that endorphins, serotonin, and dopamine do. Exercise, Mechoulam notes, has been shown to elevate endocannabinoid levels in the brain, and “this probably accounts for what jogging enthusiasts call runner’s high.” These compounds, he explains, apparently play an important role in such basic functions as memory, balance, movement, immune health, and neuroprotection.Typically, pharmaceutical companies making cannabis-based medicines have sought to isolate individual compounds from the plant. But Mechoulam strongly suspects that in some cases those chemicals would work much better in concert with other compounds found in marijuana. He calls this the entourage effect, and it’s just one of the many cannabis mysteries that he says require further study. “We have just scratched the surface,” he says, “and I greatly regret that I don’t have another lifetime to devote to this field, for we may well discover that cannabinoids are involved in some way in all human diseases.”The Botanist: Into the LightThe 44,000-square-foot building hulks across from a police station in an industrial part of Denver, along a gritty stretch of converted warehouses that’s come to be known as the Green Mile. There’s nothing to indicate the nature of the enterprise. The door buzzes open, and I’m met by the chief horticulturist of Mindful, one of the largest cannabis companies in the world. A druidlike 38-year-old with keen blue eyes, Phillip Hague wears fatigues, hiking boots, and the incredulous grin of someone who—through a confluence of events he never imagined possible—has found his exact life’s calling.Hague is a self-described plantsman, a dirty-thumbed gardener since he was eight and a devotee of the great agricultural scientist Luther Burbank. For years Hague grew poinsettias, caladiums, chrysanthemums, and other plants at his family’s nursery in Texas. But now his attentions are lavished on much more lucrative buds.He leads me through Mindful’s bustling front offices and into its interior corridors. In freezers Mindful stores seeds from all over—Asia, India, North Africa, the Caribbean. A world traveler who’s become something of a Johnny Appleseed for marijuana, Hague is extremely interested in the plant’s historical biodiversity, and his seed bank of rare, wild, and ancient strains is a significant part of Mindful’s intellectual property. “We have to recognize that humans evolved with it practically since the dawn of time,” he says. “It’s older than writing. Cannabis use is part of us, and it always has been. It spread from Central Asia after the last ice age and went out across the planet with man.”Hague joined Colorado’s green revolution nearly at the beginning. When the U.S. Justice Department announced in 2009 that it would not focus on prosecuting people who complied with state medical marijuana laws, he looked at his wife and said, “We’re moving to Denver.” Now he runs one of the world’s most prominent “grows,” where more than 20,000 cannabis plants thrive.We file past the curing rooms and down a hallway pulsating with pumps, fans, filters, generators, trimming machines. A forklift trundles by. Surveillance cameras capture everything, as young workers in medical scrubs scurry about, their faces lit with the pressure and promise of an unorthodox business that’s boomed beyond comprehension. Mindful has big plans to expand, building similar facilities in other states. “Pot is hot!” Hague says with a laugh that conveys amazement and exhaustion. “I’m blown away by what’s happening here every single day.”He throws open an industrial door, and my eyeballs are scalded by a halo of plasma bulbs. We step into an immense, warm room that smells like a hundred Yes concerts. Once my eyes adjust, I can see the crop in all its rippling glory—close to a thousand female plants standing six feet tall, their roots bathed in a soup of nutrients, their spiky leaves nodding in the breeze of the oscillating fans. Here in a sweep of the eye is more than a half million dollars’ worth of artisanal pot.I lean over to sniff one of the powdery, tightly clustered flower buds, purple-brown and coursing with white wisps. These tiny trichomes fairly ooze with cannabinoid-rich resin. This strain is called Highway Man, after a Willie Nelson song. Hybridized by Hague, it’s a variety loaded with THC. The best parts will be trimmed by hand, dried, cured, and packaged for sale at one of Mindful’s dispensaries. “This whole room will be ready for harvest in just a few days,” Hague notes with the subtle smirk of a competitive breeder who’s won international awards for his strains.But Hague has something else he wants to show me. He leads me into a moist propagation room, where a young crop is taking root in near darkness. These babies, tagged with yellow labels, are being grown strictly for medical purposes. They’re all clones, cuttings from a mother plant. Hague is proud of this variety, which contains almost no THC but is rich in CBD and other compounds that have shown at least anecdotal promise in treating such diseases and disorders as multiple sclerosis, psoriasis, post-traumatic stress disorder, dementia, schizophrenia, osteoporosis, and amyotrophic lateral sclerosis (Lou Gehrig’s disease).“It’s these low-THC strains that really keep me up at night, dreaming about what they can do,” Hague says, noting that marijuana contains numerous substances—cannabinoids, flavonoids, terpenes—that have never been investigated in depth. “It sounds hokey,” he says as he caresses one of the cuttings like a gloating father, “but I believe cannabis has a consciousness. It’s tired of being persecuted. It’s ready to step out into the light.”The Biochemist: Miracle Cure?By now nearly everyone has heard that cannabis can play a palliative role for cancer sufferers, especially in alleviating some of the nasty side effects of chemotherapy. There’s no question that pot can stave off nausea, improve appetite, and help with pain and sleep. But could it cure cancer? Troll the Internet and you’ll see hundreds, if not thousands, of such claims. A gullible Googler could easily believe we’re on the brink of a miracle cure.The majority of these claims are anecdotal at best and fraudulent at worst. But there are also mentions of laboratory evidence pointing to cannabinoids as possible anticancer agents, and many of these reports lead to a lab in Spain run by a thoughtful, circumspect man named Manuel Guzmán.Guzmán is a biochemist who’s studied cannabis for about 20 years. I visit him in his office at the Complutense University of Madrid, in a golden, graffiti-splotched building on a tree-lined boulevard. A handsome guy in his early 50s with blue eyes and shaggy brown hair tinged with gray, he speaks rapidly in a soft voice that makes a listener lean forward. “When the headline of a newspaper screams, ‘Brain Cancer Is Beaten With Cannabis!’ it is not true,” he says. “There are many claims on the Internet, but they are very, very weak.”He blinks thoughtfully, then turns to his computer. “However, let me show you something.” On his screen flash two MRIs of a rat’s brain. The animal has a large mass lodged in the right hemisphere, caused by human brain tumor cells Guzmán’s researchers injected. He zooms in. The mass bulges hideously. The rat, I think, is a goner. “This particular animal was treated with THC for one week,” Guzmán continues. “And this is what happened afterward.” The two images that now fill his screen are normal. The mass has not only shrunk—it’s disappeared. “As you can see, no tumor at all.”In this study Guzmán and his colleagues, who’ve been treating cancer-riddled animals with cannabis compounds for 15 years, found that the tumors in a third of the rats were eradicated and in another third, reduced. This is the kind of finding that gets the world excited, and Guzmán constantly worries that his breakthrough research may give cancer sufferers false hope—and fuel specious Internet claims. “The problem is,” he says, “mice are not humans. We do not know if this can be extrapolated to humans at all.”Guzmán leads me around his cramped lab—centrifuges, microscopes, beakers, petri dishes, a postdoc researcher in a white smock extracting tissue from a mouse corpse pinned under bright lights. It’s your typical bioresearch lab, except that everything is devoted to the effects of cannabis on the body and brain. The lab focuses not just on cancer but also on neurodegenerative diseases and on how cannabinoids affect early brain development. On this last topic the Guzmán group’s research is unequivocal: Mice born of mothers regularly given high doses of THC during pregnancy show pronounced problems. They’re uncoordinated, have difficulty with social interactions, and have a low anxiety threshold—they’re often paralyzed with fear at stimuli, such as a cat puppet placed near their cage, that don’t upset other juvenile mice.The lab also has studied how the chemicals in cannabis, as well as cannabinoids like the anandamide produced by our bodies, protect our brains against various types of insults, such as physical and emotional trauma. “Our brain needs to remember things, of course,” says Guzmán, “but it also needs to forget things—horrific things, unnecessary things. It’s much like the memory in your computer—you have to forget what is not necessary, just like you need to periodically delete old files. And you have to forget what is not good for your mental health—a war, a trauma, an aversive memory of some kind. The cannabinoid system is crucial in helping us push bad memories away.”But it’s Guzmán’s brain tumor research that has captured headlines—and the interest of pharmaceutical companies. Through his years of research he has ascertained that a combination of THC, CBD, and temozolomide (a moderately successful conventional drug) works best in treating brain tumors in mice. A cocktail composed of these three compounds appears to attack brain cancer cells in multiple ways, preventing their spread but also triggering them, in effect, to commit suicide.Now a groundbreaking clinical trial based on Guzmán’s work is under way at St. James’s University Hospital, in Leeds, England. Neuro-oncologists are treating patients who have aggressive brain tumors with temozolomide and Sativex, a THC-CBD oral spray developed by GW Pharmaceuticals.Guzmán cautions against overoptimism but welcomes the beginning of human studies. “We have to be objective,” he says. “At least the mind-set is opening around the world, and funding agencies now know that cannabis, as a drug, is scientifically serious, therapeutically promising, and clinically relevant.”Will cannabis help fight cancer? “I have a gut feeling,” he says, “that this is real.”Cannabis is a family business for Ben and Megan Schwarting and their three daughters in Washington State, where voters legalized marijuana in 2012. On a breathtaking ledge in Gig Harbor overlooking Puget Sound, Megan makes lotions, and Ben makes concentrated oils. His mother, Mari, Grows marijuana in her basement, and sometimes her granddaughters help prepare the soil. Megan made her first cannabis products in her late teens, at a time when Ben was growing pot in South Dakota. She jokes, "We each had a grown light, and that's what we brought to the relationship."The Caregiver: Medical MigrantsThe seizures started in May 2013 when she was six months old. Infantile spasms, they were called. It looked like a startle reflex—her arms rigid at her side, her face a frozen mask of fear, her eyes fluttering from side to side. Addelyn Patrick’s little brain raced and surged, as though an electromagnetic storm were sweeping through it. “It’s your worst possible nightmare,” her mother, Meagan, says. “Just awful, awful, awful to watch your child in pain, in fear, and there’s nothing you can do to stop it.”From their small town in southwestern Maine, Meagan and her husband, Ken, took Addy to Boston to consult with neurologists. These epileptic seizures, they concluded, were the result of a congenital brain malformation called schizencephaly. One of the hemispheres of Addy’s brain had not developed fully in utero, leaving an abnormal cleft. She also had a related condition called optic nerve hypoplasia, which caused her eyes to wander—and which, further tests revealed, made her all but blind. By summer Addy was having 20 to 30 seizures a day. Then 100 a day. Then 300. “Everything was misfiring all at once,” says Meagan. “We were afraid we were going to lose her.”The Patricks followed the advice they’d been given and heavily medicated Addy with anticonvulsants. The powerful meds reduced her seizures, but they also put her to sleep for almost the entire day. “Addy was gone,” Meagan says. “She just lay there, sleeping all the time. Like a rag doll.”Meagan quit her job as a third-grade teacher to care for her daughter. Over nine months Addy was hospitalized 20 times.When Meagan’s in-laws suggested they look into medical marijuana, she recoiled. “This is a federally illegal drug we are talking about,” she recalls thinking. But she did her own research. A good deal of anecdotal evidence shows that high-CBD strains of cannabis can have a strong antiseizure effect. The medical literature, though scant, goes back surprisingly far. In 1843 a British doctor named William O’Shaughnessy published an article detailing how cannabis oil had arrested an infant’s relentless convulsions.In September 2013 the Patricks met with Elizabeth Thiele, a pediatric neurologist at Boston’s Massachusetts General Hospital who’s helping lead a study of CBD in treating refractory childhood epilepsy. Legally, Thiele could not prescribe cannabis to Addy or even recommend it. But she strongly advised the Patricks to consider all medical options.Encouraged, Meagan went to Colorado and met with parents whose epileptic children were taking a strain of cannabis called Charlotte’s Web, named for a little girl, Charlotte Figi, who’d responded astonishingly well to the low-THC, high-CBD oil produced near Colorado Springs.What Meagan saw in Colorado impressed her—the growing knowledge base of cannabis producers, the kinship of parents coping with similar ordeals, the quality of the dispensaries, and the expertise of the test labs in ensuring consistent cannabis-oil formulations. Colorado Springs had become a mecca for a remarkable medical migration. More than a hundred families with children who had life-threatening medical conditions had uprooted themselves and moved. These families, many of them associated with a nonprofit organization called the Realm of Caring, consider themselves “medical refugees.” Most couldn’t medicate their children with cannabis in their home states without risking arrest for trafficking or even child abuse.Meagan experimented with high-CBD oil. The seizures all but stopped. She weaned Addy off some of her other meds, and it was as though she’d come back from a coma. “It sounds like a small thing,” says Meagan. “But if you have a child who smiles for the first time in many, many months, well, your whole world changes.”By early last year the Patricks had made up their minds. They would move to Colorado to join the movement. “It was a no-brainer,” Meagan says. “If they were growing something on Mars that might help Addy, I’d be in my backyard building a spaceship.”When I meet the Patricks in late 2014, they’ve settled into their new home on the north side of Colorado Springs. Pikes Peak looms in their living room window. Addy is thriving. Since first taking CBD oil, she hasn’t been hospitalized. She still has occasional seizures—one or two a day—but they’re less intense. Her eyes wander less. She listens more. She laughs. She’s learned how to hug and has discovered the power of her vocal cords.Critics contend that the Realm of Caring parents are using their kids as guinea pigs, that not enough studies have been done, that many, if not most, of the claims can be dismissed as the result of the placebo effect. “It’s true, we don’t know the long-term effects of CBD, and we should study it,” Meagan says. “But I can tell you this. Without it, our Addy would be a sack of potatoes.” No one asks, she notes, about the long-term effects of a widely used pharmaceutical that has been routinely prescribed for her two-year-old. “Our insurance pays for it, no questions asked,” she says. “But it’s highly addictive, highly toxic, turns you into a zombie, and can actually kill you. And yet it’s perfectly legal.”Thiele says early results of the CBD study are extremely encouraging. “CBD is not a silver bullet—it doesn’t work for everybody,” she cautions. “But I’m impressed. It clearly can be a very effective treatment for many people. I have several kids in the study who’ve been completely seizure free for over a year.”Reports like these only deepen Meagan’s frustrations with what she has come to regard as the imbecility of federal marijuana laws that put her at risk of arrest for transporting a drug that “wouldn’t get a mouse high” across state lines. “It’s unacceptable,” she says, “that we’re allowing our citizens to suffer like this.”But the Patricks are in a good place now—happier than they’ve been in years. “We have Addy back again,” Meagan says. “If I wasn’t living through this, I don’t know that I’d believe it myself. I don’t feel like cannabis is a miracle cure. But I feel like it should be a tool in every neurologist’s toolbox, all around the country.” The Geneticist: Building the Map“It’s such an interesting plant, such a valuable plant,” says Nolan Kane, who specializes in evolutionary biology. “It’s been around for millions of years, and it’s one of man’s oldest crops. And yet there are so many basic problems that need to be answered. Where did it come from? How and why did it evolve? Why does it make all these suites of compounds? We don’t even know how many species there are.”We’re standing in a laboratory greenhouse on the campus of the University of Colorado Boulder looking at ten hemp plants that Kane recently procured for research purposes. They’re spindly, stalky little things, like gangling teenagers, a far cry from the lascivious crop that Hague had shown me. These plants, like nearly all hemp varieties, carry extremely low levels of THC.They may not look threatening, but their very presence here, in the confines of a major university lab, represents years of wrangling to win federal and university approval. Right now, Kane’s allowed to grow only hemp strains. The rest of his research material is cannabis DNA, which is supplied by Colorado growers who extract it using methods he’s taught them.Kane fingers one of his innocuous-looking plants, expressing mild bemusement at the U.S. ban on commercial hemp cultivation. “Hemp produces fibers of unparalleled quality,” he notes. “It’s a tremendously high biomass crop that replenishes the soil and doesn’t require much in terms of inputs. We import tons and tons of hemp each year from China and even Canada, yet as a matter of federal policy, we can’t legally grow it. There are places where farmers in the U.S. can literally look across the Canadian border and see fields that are yielding huge profits.”A geneticist, Kane studies cannabis from a unique perspective—he probes its DNA. He’s an affable, outdoorsy guy with a bright face and eyes that wander and dart inquisitively when he talks. He has studied chocolate and for many years the sunflower, eventually mapping its genome, a sequence of more than three and a half billion nucleotides. Now he’s moved on to marijuana. Though its sequence is much shorter, roughly 800 million nucleotides, he considers it a far more intriguing plant.A sketchy outline of the cannabis genome already exists, but it’s highly fragmented, scattered into about 60,000 pieces. Kane’s ambitious goal, which will take many years to achieve, is to assemble those fragments in the right order. “The analogy I use is, we have 60,000 pages of what promises to be an excellent book, but they’re strewn all over the floor,” he says. “We have no idea yet how those pages fit together to make a good story.”Many people are more than a little eager to learn how Kane’s story will play out. “There’s a certain pressure,” he says, “because this work will have huge implications, and anything we do in this lab will be under a lot of scrutiny. You can feel it. People are just wanting this to happen.”Once the map is complete, enterprising geneticists will be able to use it in myriad ways, such as breeding strains that contain much higher levels of one of the plant’s rare compounds with medically important properties. “It’s like discovering some hidden motif deep in a piece of music,” Kane says. “Through remixing, you can accentuate it and turn it up so that it becomes a prominent feature of the song.”As Kane leads me around his lab, I see the excitement on his face and on the faces of his young staff. The place feels almost like a start-up company. “So much of science is incremental,” he says, “but with this cannabis work, the science will not be incremental. It will be transformative. Transformative not just in our understanding of the plant but also of ourselves—our brains, our neurology, our psychology. Transformative in terms of the biochemistry of its compounds. Transformative in terms of its impact across several different industries, including medicine, agriculture, and biofuels. It may even transform part of our diet—hemp seed is known to be a ready source of a very healthy, protein-rich oil. ”Cannabis, Kane says, “is an embarrassment of riches.” http://www.nationalgeographic.com/magazine/2015/06/marijuana-science-drug-research-legality/




Introduction to the Endocannabinoid System


Dustin Sulak, DO As you read this review of the scientific literature regarding the therapeutic effects of cannabis and cannabinoids, one thing will become quickly evident: cannabis has a profound influence on the human body. This one herb and its variety of therapeutic compounds seem to affect every aspect of our bodies and minds. How is this possible? At our integrative medical clinics in Maine and Massachusetts, my colleagues and I treat over 18,000 patients with a huge diversity of diseases and symptoms. In one day I might see cancer, Crohn's disease, epilepsy, chronic pain, multiple sclerosis, insomnia, Tourette's syndrome and eczema, just to name a few. All of these conditions have different causes, different physiologic states, and vastly different symptoms. The patients are old and young. Some are undergoing conventional therapy. Others are on a decidedly alternative path. Yet despite their differences, almost all of my patients would agree on one point: cannabis helps their condition. As a physician, I am naturally wary of any medicine that purports to cure-all. Panaceas, snake-oil remedies, and expensive fads often come and go, with big claims but little scientific or clinical evidence to support their efficacy. As I explore the therapeutic potential of cannabis, however, I find no lack of evidence. In fact, I find an explosion of scientific research on the therapeutic potential of cannabis, more evidence than one can find on some of the most widely used therapies of conventional medicine. At the time of updating (February 2015), a PubMed search for scientific journal articles published in the last 20 years containing the word "cannabis" revealed 8,637 results. Add the word "cannabinoid," and the results increase to 20,991 articles. That's an average of more than two scientific publications per day over the last 20 years! These numbers not only illustrate the present scientific interest and financial investment in understanding more about cannabis and its components, but they also emphasize the need for high quality reviews and summaries such as the document you are about to read. How can one herb help so many different conditions? How can it provide both palliative and curative actions? How can it be so safe while offering such powerful effects? The search to answer these questions has led scientists to the discovery of a previously unknown physiologic system, a central component of the health and healing of every human and almost every animal: the endocannabinoid system.

What Is The Endocannabinoid System?
The endogenous cannabinoid system, named after the plant that led to its discovery, is perhaps the most important physiologic system involved in establishing and maintaining human health. Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. In each tissue, the cannabinoid system performs different tasks, but the goal is always the same: homeostasis, the maintenance of a stable internal environment despite fluctuations in the external environment. Cannabinoids promote homeostasis at every level of biological life, from the sub-cellular, to the organism, and perhaps to the community and beyond. Here's one example: autophagy, a process in which a cell sequesters part of its contents to be self-digested and recycled, is mediated by the cannabinoid system. While this process keeps normal cells alive, allowing them to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products, it has a deadly effect on malignant tumor cells, causing them to consume themselves in a programmed cellular suicide. The death of cancer cells, of course, promotes homeostasis and survival at the level of the entire organism. Endocannabinoids and cannabinoids are also found at the intersection of the body's various systems, allowing communication and coordination between different cell types. At the site of an injury, for example, cannabinoids can be found decreasing the release of activators and sensitizers from the injured tissue, stabilizing the nerve cell to prevent excessive firing, and calming nearby immune cells to prevent release of pro-inflammatory substances. Three different mechanisms of action on three different cell types for a single purpose: minimize the pain and damage caused by the injury. The endocannabinoid system, with its complex actions in our immune system, nervous system, and all of the body's organs, is literally a bridge between body and mind. By understanding this system we begin to see a mechanism that explains how states of consciousness can promote health or disease. In addition to regulating our internal and cellular homeostasis, cannabinoids influence a person's relationship with the external environment. Socially, the administration of cannabinoids clearly alters human behavior, often promoting sharing, humor, and creativity. By mediating neurogenesis, neuronal plasticity, and learning, cannabinoids may directly influence a person's open-mindedness and ability to move beyond limiting patterns of thought and behavior from past situations. Reformatting these old patterns is an essential part of health in our quickly changing environment.
What Are Cannabinoid Receptors?
Sea squirts, tiny nematodes, and all vertebrate species share the endocannabinoid system as an essential part of life and adaptation to environmental changes. By comparing the genetics of cannabinoid receptors in different species, scientists estimate that the endocannabinoid system evolved in primitive animals over 600 million years ago. While it may seem we know a lot about cannabinoids, the estimated twenty thousand scientific articles have just begun to shed light on the subject. Large gaps likely exist in our current understanding, and the complexity of interactions between various cannabinoids, cell types, systems and individual organisms challenges scientists to think about physiology and health in new ways. The following brief overview summarizes what we do know. Cannabinoid receptors are present throughout the body, embedded in cell membranes, and are believed to be more numerous than any other receptor system. When cannabinoid receptors are stimulated, a variety of physiologic processes ensue. Researchers have identified two cannabinoid receptors: CB1, predominantly present in the nervous system, connective tissues, gonads, glands, and organs; and CB2, predominantly found in the immune system and its associated structures. Many tissues contain both CB1 and CB2 receptors, each linked to a different action. Researchers speculate there may be a third cannabinoid receptor waiting to be discovered. Endocannabinoids are the substances our bodies naturally make to stimulate these receptors. The two most well understood of these molecules are called anandamide and 2-arachidonoylglycerol (2-AG).They are synthesized on-demand from cell membrane arachidonic acid derivatives, have a local effect and short half-life before being degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Phytocannabinoids are plant substances that stimulate cannabinoid receptors. Delta-9-tetrahydrocannabinol, or THC, is the most psychoactive and certainly the most famous of these substances, but other cannabinoids such as cannabidiol (CBD) and cannabinol (CBN) are gaining the interest of researchers due to a variety of healing properties. Most phytocannabinoids have been isolated from cannabis sativa, but other medical herbs, such as echinacea purpura, have been found to contain non-psychoactive cannabinoids as well. Interestingly, the cannabis plant also uses THC and other cannabinoids to promote its own health and prevent disease. Cannabinoids have antioxidant properties that protect the leaves and flowering structures from ultraviolet radiation - cannabinoids neutralize the harmful free radicals generated by UV rays, protecting the cells. In humans, free radicals cause aging, cancer, and impaired healing. Antioxidants found in plants have long been promoted as natural supplements to prevent free radical harm. Laboratories can also produce cannabinoids. Synthetic THC, marketed as dronabinol (Marinol), and nabilone (Cesamet), a THC analog, are both FDA approved drugs for the treatment of severe nausea and wasting syndrome. Some clinicians have found them helpful in the off-label treatment of chronic pain, migraine, and other serious conditions. Many other synthetic cannabinoids are used in animal research, and some have potency up to 600 times that of THC.
Cannabis, The Endocannabinoid System, And Good Health
As we continue to sort through the emerging science of cannabis and cannabinoids, one thing remains clear: a functional cannabinoid system is essential for health. From embryonic implantation on the wall of our mother's uterus, to nursing and growth, to responding to injuries, endocannabinoids help us survive in a quickly changing and increasingly hostile environment. As I realized this, I began to wonder: can an individual enhance his/her cannabinoid system by taking supplemental cannabis? Beyond treating symptoms, beyond even curing disease, can cannabis help us prevent disease and promote health by stimulating an ancient system that is hard-wired into all of us? I now believe the answer is yes. Research has shown that small doses of cannabinoids from cannabis can signal the body to make more endocannabinoids and build more cannabinoid receptors. This is why many first-time cannabis users don't feel an effect, but by their second or third time using the herb they have built more cannabinoid receptors and are ready to respond. More receptors increase a person's sensitivity to cannabinoids; smaller doses have larger effects, and the individual has an enhanced baseline of endocannabinoid activity. I believe that small, regular doses of cannabis might act as a tonic to our most central physiologic healing system. Many physicians cringe at the thought of recommending a botanical substance, and are outright mortified by the idea of smoking a medicine. Our medical system is more comfortable with single, isolated substances that can be swallowed or injected. Unfortunately, this model significantly limits the therapeutic potential of cannabinoids. Unlike synthetic derivatives, herbal cannabis may contain over one hundred different cannabinoids, including THC, which all work synergistically to produce better medical effects and less side effects than THC alone. While cannabis is safe and works well when smoked, many patients prefer to avoid respiratory irritation and instead use a vaporizer, cannabis tincture, or topical salve. Scientific inquiry and patient testimonials both indicate that herbal cannabis has superior medical qualities to synthetic cannabinoids. In 1902 Thomas Edison said, "There were never so many able, active minds at work on the problems of disease as now, and all their discoveries are tending toward the simple truth that you can't improve on nature." Cannabinoid research has proven this statement is still valid. So, is it possible that medical cannabis could be the most useful remedy to treat the widest variety of human diseases and conditions, a component of preventative healthcare, and an adaptive support in our increasingly toxic, carcinogenic environment? Yes. This was well known to the indigenous medical systems of ancient India, China, and Tibet, and as you will find in this report, is becoming increasingly well known by Western science. Of course, we need more human-based research studying the effectiveness of cannabis, but the evidence base is already large and growing constantly, despite the DEA's best efforts to discourage cannabis-related research. Does your doctor understand the benefit of medical cannabis? Can he or she advise you in the proper indications, dosage, and route of administration? Likely not. Despite the two largest U.S. physician associations (American Medical Association and American College of Physicians) calling for more research, the U.S. Congress prohibiting federal interference in states' medical cannabis programs, a 5,000 year history of safe therapeutic use, and a huge amount of published research, most doctors know little or nothing about medical cannabis. This is changing, in part because the public is demanding it. People want safe, natural and inexpensive treatments that stimulate our bodies' ability to self-heal and help our population improve its quality of life. Medical cannabis is one such solution. This summary is an excellent tool for spreading the knowledge and helping to educate patients and healthcare providers on the scientific evidence behind the medical use of cannabis and cannabinoids. http://norml.org/library/item/introduction-to-the-endocannabinoid-system




Clinical Endocannabinoid Deficiency Reconsidered


By Ethan Russo, M.D. On August 02, 2016 Ethan Russo Endocannabinoid deficiency Abstract (Cannabis and Cannabinoid Research) 2016 Dr. Ethan Russo examines recent science on migraine, fibromyalgia, irritable bowel and other treatment-resistant syndromes that may respond to cannabinoid therapies. 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. https://www.projectcbd.org/about/laboratorypreclinical-studies/clinical-endocannabinoid-deficiency-reconsidered




The Ensemble Effect, Not the Entourage Effect


By Rick Thompson March 17, 2016 It’s a popular theme in marijuana use – the “entourage effect.” It’s defined as the broad-spectrum sense of wellness derived from consuming an unaltered or concentrated form of cannabis. All the natural chemicals found in cannabis are ingested simultaneously. Any single chemical in isolation does not perform in the same way that a substance will when associated with other chemicals found in the original, natural source. The three primary components of the marijuana chemical cocktail include CBD, THC and the phytocannabinoid group of terpenoids. CBD by itself performs different than CBD in conjunction with THC, and both perform differently when in the presence of terpenoids. Marijuana’s strength and effect varies by strain based on the ratio of these three components, among other factors. “It’s a mixture of CBD, cannabidiol, THC and the phytochemicals, the terpenoids,” says Harvard Professor, Dr. Lester Grinspoon. “You need all three of them to get the best therapeutic effect.” But Dr. Grinspoon says that he entourage effect, the broad-based experience cannabis users have when they consume marijuana containing all three components, is improperly named, Grinspoon told listeners of the Planet Green Trees Radio Show on Thursday, March 10. He prefers the term “therapeutic ensemble.” “I think that the ensemble is a better idea than entourage, because the word ‘entourage’ implies one item moving in this direction – and it has company,” Dr. Grinspoon explained, “and it is [the item] that is responsible for that activity, and the others just go along. That’s entourage. “The word ‘ensemble’” he continued, “means that these are the three things that are required for the best therapeutic effect, but you can manipulate the percentage of two of them.” Those are THC and CBD, Dr. Grinspoon stated. “The phytochemicals, the terpenoids, they come with it, as long as it is derived from the bud, from the plant and not from some oil where all the phytochemicals have been distilled out. As long as you are getting it from the bud you can manipulate by mixing strains.” Dr. Grinspoon illustrated the advantage of the therapeutic ensemble, and the effect seen when it is absent: “Cannabidiol is a non-psychoactive cannabinoid, which in fact opposes tetrahydrocannabinol, the psychoactive. If you take a large dose of CBD for therapy during the day and you try to use THC at night you won’t get high. On the other hand, you can make the THC high compared to the CBD, the ratio is reversed, and you will get a high. As long as you have the two of them, and the phytochemicals, the terpenoids, you will get a therapeutic effect.” Charlotte’s Web, a strain of cannabis known for its high CBD and low THC ratio, was cited by Dr. Grinspoon as an example of plant manipulation to express effect. “People can use [that strain] for therapeutic utility and they won’t get high, and that’s great. On the other hand, there are some people who like to have more THC in it so they get somewhat of a high, because high equals antidepressant for some people and that is very important.” The therapeutic ensemble is the key to maximizing medicinal effect. “In the world of the future we’re gonna have this therapeutic ensemble. You’ll be able to go into the medical store… and you can get a mix where you get the right ratio of cannabidiol to THC,” Dr. Grinspoon opined. “As long as that has terpenoids with it, it will be therapeutic.” Advances in marijuana testing are making medicinal cannabis use more user-friendly by identifying the product’s ratio of components. Patients can look past flashy names to find medicine that will deliver consistent, predictable effects. “It will be very easy for [medical marijuana patients] to pick it out because it isn’t the name of the strain; it’s how much of these three constituents the marijuana-based medicine contains,” Dr. Grinspoon said. One group that could benefit from this kind of targeted therapy: veterans. “PTSD is very responsive to cannabis,” Dr. Grinspoon related to PGT host, attorney Michael Komorn. Dr. Grinspoon is a pioneer in marijuana science. During the interview he discussed some of his earliest experiences with marijuana and how they were influenced – some might say, peer-pressured – by a young Carl Sagan.




Cannabis' Entourage Effect: Why Whole Plant Medicine Matters


Bailey Rahn October 28, 2015 Take a close look at your cannabis buds. They’re covered in a sticky dusting of crystal resin, which contains hundreds of therapeutic compounds known as cannabinoids and terpenoids. We assume you’re well acquainted with THC and CBD, but these are just two among many important players working together to produce specific effects. This interactive synergy between cannabis compounds has been coined the “entourage effect,” and once you know what this is, you’ll see why medicines containing only THC or CBD aren’t always sufficient for many medical conditions.

What Are THC- and CBD-Only Medicines?

THC-only medicines primarily refer to synthetic renderings of THC, the two most popular being Marinol (dronabinol) and Cesamet (nabilone). These are legal pharmaceuticals primarily prescribed to treat cancer-related nausea, but their efficacy is questionable. A 2011 survey on forms of consumption found only 1.8% of 953 patients prefer synthetic THC pharmaceuticals over inhaled or infused methods. Furthermore, it can take hours for a THC-only pill to deliver relief whereas inhaled methods take effect immediately. CBD-only medicines have been gaining momentum in recent years following the media frenzy around Charlotte’s Web, a non-psychoactive cannabis strain that was processed into a CBD-rich oil for an epileptic child. The miraculous remedy prompted several states to adopt CBD-only laws under which THC-rich medicines remain illegal. While CBD-only cannabis medicines have proven to be life-changing for many individuals, these laws mainly exist to help those suffering from seizures. That is not to say that synthetic, hemp-based, and CBD-only medicines aren’t effective options for many patients, especially as laws limit access to alternatives. These types of products have served a monumental role both as medicine and as a legislative stepping stone. But what more can patients get from whole plant medicine?

What Makes “Whole Plant Medicine” Different?

“Whole plant medicine” is a term used to describe medicines utilizing the full spectrum of therapeutic compounds cannabis has to offer. A glimpse of the most abundant cannabinoids and terpenes is provided below in our two graphics illustrating the properties and benefits of each. Each of these therapeutic agents that are processed out of THC- and CBD-only medicines have so much to offer patients treating a wide breadth of symptoms and conditions. You’re already familiar with the most popular “whole plant medicine,” which is inhaling cannabis smoke or vapor. Although most cannabis today is bred to contain a disproportionately large amount of THC compared to other compounds, the importance of chemical diversity is being realized as new strains emerge. Hopefully, we’ll soon start to see strains that not only narrow the gap between THC and CBD profiles, but emphasize other important cannabinoids and terpenes as well.

Cannabinoids and Terpenes Work Together

The diverse chemical availability in whole plant medicines is remarkable in its own right, but research looking into how cannabinoids and terpenoids work together adds another level of intrigue. Instrumental in this area of science is Ethan Russo, M.D., a neurologist who has long studied cannabis compounds and their role in the body. In his study “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects,” he details how cannabis compounds influence each other’s mechanisms. We aren’t just talking about the well-known THC-CBD tag team here – even small amounts of terpenes (fragrant oils that give cannabis its smell) can make a difference. The terpene myrcene, for example, can reduce resistance in the blood-brain barrier, enabling easier passage of other beneficial chemicals. Pinene helps counteract compromised cognition and memory caused by THC. A combination of terpenes pinene, myrcene, and caryophyllene help unravel anxiety. Mixing terpenes linalool and limonene with the cannabinoid CBG shows promise in the treatment of MRSA. THC plus CBN yields enhanced sedating effects. Linalool and limonene combined with CBD is being examined as an anti-acne treatment. These examples only scratch the surface of all possible synergies made available to us by way of whole plant therapies. Think of all the medical possibilities waiting for us as the combinational potential of these compounds are unlocked. The thought of how many lives could be changed for the better by such discoveries is almost overwhelming. https://www.leafly.com/news/cannabis-101/cannabis-entourage-effect-why-thc-and-cbd-only-medicines-arent-g





Medical Marijuana and the "Entourage Effect" by Sanjay Gupta


By Dr. Sanjay Gupta, CNN chief medical correspondent Updated 1758 GMT (0158 HKT) March 11, 2014 In the early 1060's a young postdoctoral student stumbled onto something that puzzled him. After reading the literature on cannabis, he was surprised to see that while the active compound in morphine had been isolated from opium poppies 100 years before and cocaine isolated from coca leaves around the same time, the active component of marijuana was still unknown. This simple observation launched his life's work. That young Israeli researcher, Raphael Mechoulam, is now a heavily decorated scientist, recently nominated for the prestigious Rothschild Prize. More than 50 years ago, however, he had trouble starting his scientific journey. For starters, he needed cannabis to study and didn't know how to obtain it. Eventually, he obtained his research supply from friends in the police department. The young scientist was in a hurry, and didn't want to wait to cut through the red tape required by Israel's Health Ministry. Dr. Sanjay Gupta is a practicing neurosurgeon and CNN's chief medical correspondent. "Yes, I broke the law," he told me when I met with him in Tel Aviv last year, "but I apologized and explained what I was trying to do." It's a good thing the Israeli government didn't stall his progress, because Mechoulam was moving at breakneck speed. By 1963, he determined the structure of cannabidiol (CBD), an important component of marijuana. A year later, he became the first person to isolate delta-9 tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana. Over the ensuing decades, Mechoulam and his team continued to isolate numerous compounds from the cannabis plant. Their work also went a long way toward illuminating how the drug works in the brain. When Mechoulam's team identified the first known endogenous cannabinoid, a chemical actually made by the brain itself, he named it "anandamide." In the Sanskrit language, ananda means "supreme bliss," which gives us some insight into what Mechoulam thinks of cannabinoids overall. It was halfway through our long afternoon discussion that Mechoulam, now 83, pulled out a paper he had written in 1999, describing something known as "the entourage effect." Think of it like this: There are more than 480 natural components found within the cannabis plant, of which 66 have been classified as "cannabinoids." Those are chemicals unique to the plant, including delta-9-tetrahydrocannabinol and cannabidiols. There are, however, many more, including: -- Cannabigerols (CBG); -- Cannabichromenes (CBC); -- other Cannabidiols (CBD); -- other Tetrahydrocannabinols (THC); -- Cannabinol (CBN) and cannabinodiol (CBDL); -- other cannabinoids (such as cannabicyclol (CBL), cannabielsoin (CBE), cannabitriol (CBT) and other miscellaneous types). Other constituents of the cannabis plant are: nitrogenous compounds (27 known), amino acids (18), proteins (3), glycoproteins (6), enzymes (2), sugars and related compounds (34), hydrocarbons (50), simple alcohols (7), aldehydes (13), ketones (13), simple acids (21), fatty acids (22), simple esters (12), lactones (1), steroids (11), terpenes (120), non-cannabinoid phenols (25), flavonoids (21), vitamins (1), pigments (2), and other elements (9). Minister's daughter: Cannabis "a gift from God" Here is the important point. Mechoulam, along with many others, said he believes all these components of the cannabis plant likely exert some therapeutic effect, more than any single compound alone. While science has not yet shown the exact role or mechanism for all these various compounds, evidence is mounting that these compounds work better together than in isolation: That is the "entourage effect." Take the case of Marinol, which is pure, synthetic THC. When the drug became available in the mid-1980s, scientists thought it would have the same effect as the whole cannabis plant. But it soon became clear that most patients preferred using the whole plant to taking Marinol. Researchers began to realize that other components, such as CBD, might have a larger role than previously realized. To better understand the concept of the entourage effect, I traveled to the secret labs of GW Pharmaceuticals, outside London. In developing Sativex, a cannabis-based drug to treat multiple sclerosis, the company's chairman, Dr. Geoffrey Guy, told me the company ran into some of the same obstacles that Marinol faced. More than a decade of experiments revealed that a whole plant extract, bred to contain roughly the same amounts of THC and CBD in addition to the other components in the plant, was more effective in reducing the pain and spasms of MS than a medication made of a single compound. It could be that multiple individual compounds play a role, or it could be due to their interaction in the body; it could also be combination of both, Guy said. Now, maybe this all sounds obvious. After all, eating real fruits, vegetables and other plants provides better nutrition than just taking vitamin pills with one nutrient or mineral in each. Science is showing us that we can likely say the same about cannabis. As we move forward with creating medicines, like Charlotte's Web, for the patients who can benefit from cannabis -- this is an important point to keep in mind. Unlike other drugs that may work well as single compounds, synthesized in a lab, cannabis may offer its most profound benefit as a whole plant, if we let the entourage effect flower, as Mechoulam suggested more than a decade ago. http://edition.cnn.com/2014/03/11/health/gupta-marijuana-entourage/




Botany of Desire - 4 plants, including Cannabis


They are four of the most ordinary plants. We've always had this idea that we are in charge, but what if, in fact, they have been modeling us? We don't give enough recognition to plants. They have been laboring on us, and they've been utilizing us for their own goals. There are four plants that have walked the road to accomplishment by fulfilling human ambitions. The tulip, by satisfying our longing for a certain kind of attractiveness, has gotten us to take it from its basis in Central Asia and distribute it around the world.

Marijuana, by satisfying our ambition to change awareness, has gotten us to risk our lives and freedom, in order to produce more of it. The potato, by fulfilling our desire for mastery, the control over surrounding, so that we can nourish ourselves has gotten itself out of South America and extended its range far beyond where it was long time ago. And the apple, by satisfying our appetite for sweetness, begins in the woods of Kazakhstan and is now the worldwide fruit. These are great champions in the game of domestication.

The bee believes it's getting the best of the deal with the blooming apple. It's getting in, it's taking the nectar and has no sense that it's picked up the pollen and is transferring it to another location. For the bee to assume that it's in charge of this friendship is really just a lack of success of bee's insight. We have the same failure of imagination. We are too working for the potatoes in some sense. We are planting them, we are giving them a habitat, and in the same time we think we're calling the shots.

Wouldn't it be appealing to look at our connection to domesticated plants from the plants' perspective? Of course, plants don't have awareness or goals, but by using our consciousness we can put ourselves in their roots to see things from their angle. When we do that, nature unexpectedly looks very different. We become aware that we're in the nature's web, not outside of it. These plants are reflectors in which we can see ourselves in a different way.




Medical Cannabis and its Effect on Human Health - A cannabis documentary





Dept of Health and Human Services USA - Medical Marijuana


People have used marijuana, also called cannabis, for a variety of health conditions for at least 3,000 years. The U.S. Food and Drug Administration (FDA) hasn’t found that marijuana is safe or effective for treating any health problems. However, some states and the District of Columbia allow its use for certain health purposes. States have legalized medical marijuana because of decisions made by voters or legislators—not because of scientific evidence of its benefits and risks.

It’s challenging to study the health effects of marijuana because of legal restrictions and variability in the concentration of the plant’s psychoactive chemicals. However, recently the Federal Government eased some research restrictions and also began providing researchers with more strains of marijuana. Currently, the quality of health research on marijuana and its components (other than two FDA-approved medications) varies widely by disease.

In January 2017, the National Academies of Sciences, Engineering, and Medicine published a report (link is external) on the health effects of marijuana and products derived from it. The report summarizes the current evidence on both therapeutic effects and harmful effects, recommends that research be done to develop a comprehensive understanding of the health effects of marijuana, and recommends that steps be taken to overcome regulatory barriers that may make it difficult to do research on marijuana’s health effects.

The National Institute on Drug Abuse (NIDA) has more information on many aspects of marijuana, including how likely people are to abuse it and how chemicals in marijuana affect our brain and body.

This page primarily focuses on the use of the marijuana plant, usually by smoking, for health-related purposes. The FDA has approved two prescription drugs, dronabinol and nabilone, based on a component of marijuana. These medications may be helpful for treating the symptoms associated with cancer or for the side effects of cancer therapies. In Europe, the United Kingdom, and Canada, a mouth and throat spray called nabiximols, which is derived directly from the marijuana plant and contains two of the plant’s components, has been licensed and approved for the relief of pain and spasticity associated with multiple sclerosis and as an addition to pain treatment for cancer patients. Studies of nabiximols are in progress in the United States.

https://nccih.nih.gov/health/marijuana




Scientists Want the Smoke to Clear on Med MJ Research


As U.S. policy lurches along, researchers say easing DEA rules could lead to big advances

Editor’s Note (8/11/16): The U.S. Drug Enforcement Administration is announcing today that it will keep marijuana illegal for any purpose (classified as a Schedule I substance under the Controlled Substances Act), but the government will soften rules for marijuana research to make it easier to grow the plant for scientific study. The following article was originally published in the lead-up to this decision.

For neuroscientist Chuanhai Cao, the problem with the U.S. Drug Enforcement Administration’s classification of marijuana as a Schedule I drug can be summed up in two words: dead mice.

Cao, a researcher at the University of South Florida’s Byrd Alzheimer’s Institute, uses transgenic mice to study the effect of the marijuana component tetrahydrocannabinol (THC) on amyloid beta, the protein that forms the plaque found in the brains of Alzheimer’s patients. Timing is critical in his work—the mice, which are difficult to breed, have to be a specific age at the time of an experiment. One Cao project, designed for 12-month-old mice, was delayed three months while the Drug Enforcement Administration (DEA) processed the complicated paperwork that all marijuana researchers must submit under the current system. Some of the mice died while Cao waited for the approvals he needed to acquire the THC for the experiment; he ended up with too few animals that were all too old to generate useful data. “It was a disaster,” he says.

The sting of that calamity, and of similar DEA-related snafus in labs around the country, could be soothed somewhat this summer if the agency decides in July to remove marijuana from its Schedule I list of controlled substances, which includes heroin, and reclassify it. “I’d be very excited to see that,” says Cao, who wants marijuana moved to Schedule III, which includes drugs like Tylenol with codeine and involves a less arduous DEA approval process.

Sachin Patel, an associate professor of psychiatry at Vanderbilt University School of Medicine who studies “the role of endogenous cannabinoids as mediators of stress resiliency,” would be satisfied with a more modest change. “Rescheduling cannabis as Schedule II will allow the research to get done that needs to be done to determine if this is going to be a good medicine, and for what,” says Patel, who has been researching cannabis for 15 years. Schedule II lists drugs deemed to have a high potential for abuse, including oxycodone or Percocet.

Marijuana is widely recognized as an often-effective treatment for a variety of common conditions. Even though it remains illegal at the federal level, 23 states and the District of Columbia have legalized its use for chronic pain, nausea, glaucoma, migraine and more. But researchers like Patel and Cao believe cannabis has even greater potential in the treatment of major disorders including Alzheimer’s, cancer, epilepsy, post-traumatic stress disorder and autoimmune diseases. They have committed their careers to it and, despite the onerous restrictions and endless hassles—Patel once waited six months for a DEA green-light—they have made real progress and routinely published their findings. A decision by the DEA to reschedule, although it will not completely remove the onus of illegality or the burden on scientists, could launch a new era in marijuana research.

“It’s not that we don’t have a lot of information,” says Lester Grinspoon, who has been researching and writing about marijuana since the 1960s and would prefer the DEA to delist it altogether. “If you go to PubMed you’ll find that there are 23,000 papers published on cannabis. But [with rescheduling] we can open it up to large, double-blind clinical studies.” Grinspoon, 87, an associate professor emeritus of psychiatry at Harvard Medical School, sees similarities to the history of another drug. “We didn’t have any large double-blind studies of penicillin until the mid-60s,” he says, “so it was all anecdotal evidence. But it came across as a wonder drug. And it was.”

Easing DEA restrictions could accelerate the pace and amount of research going on, including the fundamental in vitro work that people like Cao do. (In a 2014 paper published in the Journal of Alzheimer’s Disease, for example, he reported that extremely low concentrations of THC could reduce the production of amyloid beta in a cellular model of Alzheimer’s.) It could also draw more scientists into the field, open up more avenues of research and make it less difficult to attract funding. And, as Patel points out, whereas rigorous, placebo-controlled clinical trials might confirm popular notions about marijuana’s effectiveness for things like pain and nausea, they could possibly disprove them if the anecdotal evidence is trumped by science. Without such testing, he says, “We don’t really know.” A more likely outcome, Grinspoon adds, is that a new wave of research unencumbered by Schedule I status will prove that marijuana is the versatile, nontoxic, inexpensive medication he has found it to be.

Of course, the DEA is not the only obstacle. Research must also follow federal regulations that are separate from the DEA’s controlled substance schedules and require the marijuana used in studies where human subjects ingest it to come from a single source: the National Center for Natural Products Research at the University of Mississippi. And a 2015 analysis done at Arizona State University found that between 2008 and 2014, of the $1.4 billion the National Institutes of Health spent on marijuana research, just $297 million was spent on potential medical uses; the rest, $1.1 billion, went for abuse and addiction studies.

Still, Grinspoon thinks DEA rescheduling could go a long way toward changing the way the medical establishment views marijuana and the value of studying it. “Miseducation about cannabis over the last 50 years has been so thorough that it’s going to take time,” he says. “But this will knock down one of those obstacles.” One possible result: “Medical schools will start to recognize that they have to teach about cannabis as an important new medicine. Of course, it’s been around for 10,000 years, but new in the sense of coming to Western medicine.”

Whether or not he gets the Schedule III decision he is hoping for, Cao will continue on the path he has followed for nearly 10 years. For him, THC research is a long-term proposition and a personal quest. “We are trying to find therapies for Alzheimer’s patients,” he says, “and my mom is an Alzheimer’s patient.” If there is any possibility that marijuana could provide an effective treatment, he’ll pursue it, no matter what regulatory hurdles he has to clear.

https://www.scientificamerican.com/article/scientists-want-the-smoke-to-clear-on-medical-marijuana-research/




Center for Medicinal Cannabis Research


Please go to this link to see the newst research completed at the Center for Medicinal Cannabis Research http://www.cmcr.ucsd.edu/index.php