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At the end of last month, the US Food & Drug Administration approved Epidiolex, a new drug to treat rare epileptic disorders. The FDA approves many new medications each year, but Epidiolex has been in the news for two reasons: Strawberry flavored syrup is designed to appeal to young children, and its active pharmaceutical ingredient – cannabidiol – comes from marijuana [19659002] Marijuana Medicine
Epidiolex is not the first cannabinoid to be approved as a drug. Marinol (dronabinol), which is simply synthetic tetrahydrocannabinol (THC), has been used to stimulate the appetite of people undergoing chemotherapy since 1985. But Epidiolex is the first drug approved by the FDA for which the active ingredient Cannabidiol is extracted from marijuana plants. 19659006] In Brief
The therapeutic potential of cannabidiol, one of the major phytochemicals found in marijuana, has been largely ignored by doctors and scientists for decades. But in recent years, its ability to treat rare seizure disorders has emerged, leading to the first FDA approval for a drug containing cannabidiol. While scientists are trying to understand the mechanism of the compound and explore its potential health benefits, some worry that the hype threatens to exceed hope. Keep reading to learn more about this cultural phenomenon.
Cannabidiol, or CBD, sprouted as a weedlike in a cultural phenomenon that has invaded its roots in medical marijuana. Dietary supplements containing varying amounts of CBD have been touted as remedies for insomnia, anxiety and pain. Beauty manufacturers also embraced the craze for CBD, adding mascara, lip balm and cannabinoid eye cream. Water and sodas impregnated with CBD promise relaxation with refreshment.
Unlike THC, the compound of marijuana that gets people up, CBD is not psychoactive. What the CBD does – and how it does it – is somewhat debatable. But scientists say that there is hope to sift through all the hype. Dozens of clinical trials are taking place to determine whether CBD is an effective treatment for a variety of disorders, while scientists are trying to understand precisely how the compound works. Now that the CBD has received the blessing of the FDA as a legitimate drug, the work, say the researchers, is just beginning
Raphael Mechoulam, an organic chemist in Hebrew The University of Jerusalem was among the first to explore the therapeutic potential of CBD. After determining the complete structure of the compound in 1963, several decades after being isolated and studied by legendary organic chemists, the interest of Roger Adams and Alexander R. Todd-Mechoulam was stung by anecdotal reports of cannabis as seasonal remedy in historical literature. He points to a fifteenth century treatise on hashish that tells the story of a poet who gave substance to the son, epilepsy, of a prominent official in Baghdad. The seizures of the son disappeared, but he had to take hashish for the rest of his life, according to the story
Although anecdotal, and possibly to be fabricated, this story prompted Mechoulam to think about the CBD. as treatment for epilepsy. He set up a collaboration with a group in Brazil and started studying CBD in animal models of epilepsy with good results. Encouraged by their success, the researchers decided to conduct a small human trial
Mechoulam isolated a half kilogram of CBD from hashish and sent it to São Paulo, Brazil, where it was used in a small study to test its effects on epilepsy. In the trial, which included 15 people with epilepsy taking antiseptic drugs, eight people received 200 to 300 mg of CBD a day for four and a half months in addition to antiseptic drugs, while seven people received a placebo . Four people in the CBD group had virtually no seizures during the trial, three others reported a partial improvement in their condition, and one person saw no change. The placebo group also experienced no change.
The results were published in 1980 at short notice. "I was surprised and disappointed that nothing is happening," says Mechoulam. Nobody has expressed interest in replicating the study or conducting a larger trial. Three decades will pbad before the research is restarted.
While the medical establishment did not notice the study of Mechulam, decades later, the results reached the parents of children with two rare forms of epilepsy: the syndrome of Dravet and Lennox-Gastaut syndrome. characterized by frequent seizures that are not usually controlled by medication. As medical marijuana became legal in some US states, these parents and other people with severe forms of epilepsy were seeking dispensaries that sold CBD-rich cannabis and low THC to treat seizures. Epilepsy of their children.
Sam Vogelstein He did not suffer from Dravet syndrome or Lennox-Gastaut syndrome, but he was diagnosed with a variant of epilepsy difficult to treat at the age of four years. By the time he was 11 years old, in 2012, his parents had tried nearly two dozen medications to reduce the number of his seizures – 5 to 20-second events in which he had partially lost consciousness, his eyes closing and his jaw released
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Sam's parents, Fred Vogelstein and Evelyn Nussenbaum, also read the literature and anecdotal reports on the CBD used to process seizures. They tried a tincture made from the so-called high-level CBD marijuana provided by a dispensary in California, where they live. But the CBD content of the offer was not reliable, so sometimes it mitigated Sam's seizures and sometimes not.
This inconsistent dose – not to mention the challenge of getting the product into states with different attitudes toward marijuana-based products. put families affected by rare forms of epilepsy in a journey to legitimize the drug. Vogelstein and Nussenbaum led the way after noting a parenthesis in the Materials and Methods section of a 2010 article in Seizure that used CBD in an animal model of epilepsy. The researchers mentioned that GW Pharmaceuticals had provided the CBD for the study. The British pharmaceutical company was already marketing Sativex, a combination of CBD and THC in equal parts, used to treat spasticity and other symptoms of multiple sclerosis. Although Sativex has not been approved in the United States, it was approved in the United Kingdom in 2010 and many other countries have followed suit
Credit : GW Pharmaceuticals
GW Pharmaceuticals fills the vials with the recently approved drug Epidiolex.
Epilepsy was not the goal of GW Pharmaceuticals in 2012, said Nussenbaum in April when she spoke to the FDA panel reviewing the drug's new drug claim. company for a cannabidiol product. "But they had greenhouses, plant material, laboratories, and they regularly and systematically extracted cannabidiol and other cannabis compounds." Nussenbaum told the panel that she had never intended to treat Sam with cannabis. "Honestly, if I had found a good science that an engine oil extract could help the seizures, I would have continued that, but I have pursued Dr. Geoffrey Guy to the place."
Nussenbaum convinced Guy, co-founder of GW, to let Sam try purified cannabidiol from GW, an epic process that Fred Vogelstein wrote about Wired in 2015. In May 2013, Sam became the first to take the drug known as Epidiolex
Epidiolex makes Sam the crises virtually disappear. Over the past two years, he has not experienced any epileptic seizures thanks to the badociation of Epidiolex and Depakote, a common adjunctive treatment for epilepsy. "Now I can understand what's happening at school, and I can have adventures that would have never been possible before.I just went to South Africa for two weeks without my parents at school. A school trip, I had a bar mitzvah 18 months ago, "he told the FDA panel in April. "I could not have done that if I had not tried this drug.That changed my life."
Sam is not the only life that Epidiolex has changed . In the past 14 months, GW Pharmaceuticals has published three clinical trials of the drug, two in the New England Journal of Medicine and one in The Lancet . In double-blind placebo controlled trials that included more than 500 patients, an oral solution of CBD, taken with other drugs, halves the number of seizures in more than 40% of children and young adults with Lennox-Gastaut syndrome.
The results were enough to get the green light from the FDA, offering for the first time a treatment for Dravet syndrome. But Nicole Villas, a former chemist who has a son with the disorder and sits on the Board of Directors of the Dravet Syndrome Foundation, notes that Epidiolex is not a cure. Some patients, like his son, do not respond to CBD. And others experience side effects, such as drowsiness, loss of appetite, diarrhea, and elevated liver enzymes, which can be a sign of liver damage.
But the fact that there is now a medicine for these children, is a huge step forward. "Having something well done, which is regulated, that can be administered in very consistent doses, and has an indication for Dravet syndrome is a wonderful thing," she says.
The scientific literature involves at least 65 distinct molecular targets for CBD. Whalley says that 50 of these targets can be excluded by considering the concentrations of CBD required to engage them. For example, he says, in a study on cells, CBD was administered at a concentration 500 times higher than it is possible to physically dose a patient. Surprisingly, scientists have also determined that CBD does not bind to the active sites of the CB1 and CB2 cannabinoid receptors, where one would expect cannabinoids to be the most active.
Regarding the anticonvulsant activity of CBD, says Whalley, "There is no data available to say that a particular molecular target is involved in the effects of CBD epilepsies human. " But animal studies have given scientists some ideas on how the compound might work, he says.
the target is the G 55 protein-coupled receptor (GPR55), which is expressed in the brain and peripheral organs. In the brain, it regulates synaptic transmission, the process that sends the signaling molecules from one neuron to the other. The connections between these brain cells are stronger when GPR55 is activated
Seizures occur when neurons become hyperactive when transmitting signals, shooting more frequently than they should. "CBD will actually block the GPR55 receptor," says Whalley, and doing so will reduce the frequency with which the neuron fires. In a model of epilepsy in rodents, animals treated without GPR55 do not respond to CBD, while those with the receptor do so
What is really needed, it is clinical data in the patients. We must see what is true hope and what is hype.
Roger Pertwee,
Professor Emeritus, University of Aberdeen
Whalley also believes that CBD could desensitize the transient potential of the type 1 vanilloid receptor (TRPV1) to dampen seizures. "If you activate a TRPV1 receptor, an ion channel opens, and in the case of a brain cell, more calcium will flow into the brain cells," he explains. . "It's actually counterproductive if you have a seizure because it will make the cell more excitable." CBD appears to activate TRPV1, but it quickly desensitizes the ion channel, blocking calcium transport in the cell. Studies show that CBD does not work well in epileptic animals designed to not express TRPV1
Finally, CBD is also known to engage a duct that carries adenosine – an anticonvulsant compound that the body manufactures . Whalley says that it is very plausible that CBD inhibits seizures via adenosine, but further experiments are needed to prove the relationship.
Whalley notes that these molecular targets are not specific to a particular type or type of crisis. Thus, he says, CBD could be used for other types of epileptic disorders, including refractory epilepsy, but that clinical work still needs to be done.
"The only truly convincing clinical evidence to date is essentially the three clinical trials where" We reported results for seizure, "Whalley said.
Because CBD appears to be able To engage as many targets, the researchers have studied its use for a number of diseases.Its interaction with the voltage-dependent anion channel 1 suggests that it might be useful for treating movement disorders, such as Parkinson's disease and its ability to interact with serotonin receptors encourages scientists to think that it might be useful for treating depression, anxiety and psychosis in bipolar disorder and schizophrenia. At low concentrations, CBD can bind to an allosteric CB1 receptor site of endocannabinoids and prevent this receptor from effectively binding THC to its active site – a mechanism that could be used to treat disorders such as obesity, where CB1 activation is excessive. by the cannabinoids made by our bodies.
But just because the CBD interacts with these receptors does not mean that it's having an effect. "What is really needed is the clinical data in patients, we have to see what is a real hope and what is the object of hype," says Roger Pertwee, professor emeritus at the University. Aberdeen and director of pharmacology at GW Pharmaceuticals, who has been studying CBD and related cannabinoids for more than 45 years. "It is much more expensive, difficult and time-consuming to do human studies, but in the end, that's what we need. "
Roger McIntyre, psychiatrist and pharmacologist at the University of Toronto, agrees." Overall, the scientific basis of cannabidiol is very strong, " He says, "Where things start to get a little thinner, it's when there are rigorous, large-scale, randomized controlled trials that are the norm in medicine." There are currently more than 40 active clinical trials on CBD. taken cocaine addiction, Parkinson's disease, and bipolar depression.
McIntyre is particularly interested in the use of CBD to treat mental illness, for which existing drugs often do not help. "There is not only an unmet need," he says. "There is a pressing, urgent and dissatisfied need for something very different" from the drugs currently available to treat mental illness. It highlights a small essay published late last year and sponsored by GW that showed that 43 people with schizophrenia who took 1000 mg of CBD a day for six weeks had fewer psychotic symptoms than those in the placebo group.
. If he's recommending using CBD to treat mental illness, his answer is a resounding no. Before he changes his answer, he wants to see more clinical data. "What is there for the CBD looks very promising, and at the same time there have been many opportunities in the past where what we thought promising in theory did not really work."
"I think that CBD has a lot of potential in many areas, but I think, "says Melanie Kelly, a pharmacologist who studies cannabinoids at Dalhousie University and the executive director of the International Cannabinoid Research Society. The hype that surrounds it probably drives him to a position where we can have expectations that go beyond the evidence we have. "
The collection of this evidence, particularly in the United States, has been a Discouraging business As a compound derived from marijuana, CBD is on the list of Schedule I substances. "Historically, this has limited the number of researchers who have access to it, says Bryan Roth, a pharmacologist who studies the mechanics Cannabinoids action at the University of North Carolina at Chapel Hill
. license for each marijuana-based compound you are studying. For example, his lab was allowed to study THC, but when they started to become interested in CBD, they had to apply for a separate license. A year pbaded before the Drug Enforcement Administration officially gave Roth the go-ahead. With obstacles like this, he says, "you have to be very motivated."
Now that the FDA has approved Epidiolex, DEA programming by the DEA will have to change. "This is good news," says Samba Reddy, who is studying the development of drugs for epilepsy and seizure disorders at the Texas A & M University. With the blessing of the FDA, Epidiolex will be soon available via medical distribution channels, he says. "This will open new frontiers for research."
This is not because CBD has recently been approved as a drug that people have not already consumed otherwise. Cannabis strains with a high content of CBD and other CBD products are available by prescription in states where medical marijuana is legal. And dietary supplements containing small amounts of CBD derived from hemp have been available at health food stores and online for several years.
Cambridge Naturals, a health and wellness store in Cambridge, Mbadachusetts, retains its vast array of CBD-based supplements enclosed in a transparent cabinet at the back of the store. Zach Milligan-Pate, who manages the supplements for the store, says that when Cambridge Naturals started selling CBD supplements and consumer products about two and a half years ago, they stocked six different products. Now, he says, they sell up to 30 different items containing CBD. Offers include liquids, capsules and beauty products
We came out of this era of complete prohibition of cannabis, probably unjustified, at this gallop without proper research.
Melanie Kelly,
Dalhousie University
Initially, according to Milligan-Pate, consumers were not very enthusiastic about these products, but over the past nine months, demand has increased significantly thanks to word of mouth. Most people, he says, are looking for CBD products to help manage stress, sleep and pain. "The CBD is currently experiencing a very intense moment," he says.
The recent trend of the CBD gives many scientists a break. "It seems to have become something that people believe to be like flaxseed oil," says Kari Franson, an expert in psychopharmacology at the University of Colorado's Skaggs School of Pharmacy & Pharmaceutical Sciences. "We need to be clearer about the fact that it's probably not a dietary supplement but rather a pharmaceutical potential." I mention this because I walked into my Colorado dog food store and that ## 147 ## I have offered CBD dog food. "
But Stuart Tomc, Vice President of Human Nutrition for CV Sciences, a company that sells CBD supplements, is not He points out that the amount of CBD in most supplements is quite low, about 15 mg per capsule.A child of 30 kg taking Epidiolex would consume up to 600 mg of CBD a day
"There is no comparison," says Tomc. "The FDA has approved 99% pure CBD for the very rare forms of epilepsy while most natural hemp extracts contain only 10 and 25% CBD. Hemp extracts consist of many different phytonutrients and natural fatty acids. These are superfoods; they are not drugs. He adds, "Our products do not treat, heal, or improve disease or disease symptoms. If you are suffering from an illness and want to use cannabidiol, we strongly encourage you to consult your pharmacist and your doctor and look for products like Epidiolex.
But Tomc also thinks that CBD consumer products have been fairly criticized. The industry, he says, which can include hundreds or even thousands of CBD products, lacks standardization.
Nicholas Vita, CEO of medical cannabis company Columbia Care, agrees that the CBD market is fractured. "You have very responsible players who go to great lengths to produce pharmaceutical grade products, and then you have a lot of" mom and pop "craft industry players trying to get there but lacking really the target. " [19659009] With so many players in the CBD market, there are bound to be bad actors. In January, the Centers for Disease Control and Prevention investigated suspected cases of intoxication in 52 people in Utah who had taken supplements labeled as containing CBD. Nine of the products tested by the CDC as a result of the outbreak of intoxication contained no CBD. Instead, the agency discovered that the products contained 4-cyano cumyl-butinaca, a synthetic cannabinoid badociated with deaths in Europe. The FDA has also cracked down on companies that claim that CBD can treat cancer.
"I see unfortunately a lot of health claims online about all things for which cannabidiol might be useful," says Robert Laprairie, who studies cannabinoid pharmacology at the University of Saskatchewan. "We are in the phase of learning and understanding cannabidiol as a medicinal entity.It is too early to make many claims."
Kelly, from Dalhousie, agrees "We came out of this era of complete prohibition of cannabis, which was probably unjustified, at this gallop without proper research," she says.
Yet, now that the CBD has gained the status of a legitimate drug, Are waiting for the cannabinoid to grow.The doctors are waiting for the results of clinical trials to see if CBD will find medicinal uses beyond rare seizure disorders, and scientists continue to unravel the complex mechanisms that give this cannabinoid its For the CBD, the long and strange journey continues
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