A friend gave me a very small sample of your Total Plant Complex, to use on what I believe may be a touch of candida left over from candidiasis that i got rid of back around 1980. And it seemed to help, but I didn’t have enough to completely get rid of it. Now I would like to order some of my own, but don’t see anywhere to order it. Also, would like to be sure this is the best form of this stuff.
Hello Ben, I’m from India. My apologies in advance for a long letter. I’ve found you article very informative and humorous also. While there are a few references to India, they are mostly of turmeric. Marijuana and Hemp recorded use in India is more than 6000 years old. You seem to have missed out on it though you do talk of Persia and early Christianity dating back to 2000 years.
Serotonin is a neurotransmitter that affects mood, social behavior, sleep, memory, appetite, and sexual function. It is believed that anxiety and depression occur when the brain isn’t properly using serotonin. 5-HT1A is a subtype of serotonin receptor, and CBD oil enhances 5-HT1A transmission. This allows for your brain to make use of the serotonin in the synaptic space, instead of it just going back into the brain. This is what makes CBD oil regulate your mood and reduce anxiety.
Because it does not produce psychoactive effects and hemp is not a controlled substance, hemp-based products are legal to sell, buy, and possess in all 50 states. However, the law is a bit more complex when discussing CBD oils and other hemp byproducts. According to the 2014 Farm Bill, hemp should only be grown and cultivated for academic research purposes. This means that, technically, any hemp-derived oil that is not grown for these purposes would be illegal — though this law is rarely enforced. To make matters more complex, the laws are somewhat unclear in certain states. Sen. Mitch McConnell of Kentucky recently introduced legislation that would legalize all hemp products at the federal level, but this decision is still pending.
The article is inaccurate. CBD oil is not mutually exclusive from hemp oil, nor is all hemp made from industrial hemp. The hemp for NatureCBD is organically grown, and the word industrial, while having a negative connotation in this industry because of the fact it implies the oil is dirty, only means to classify that the hemp is grown for production (hemp fibers, basts etc). The oil in NatureCBD is indeed CBD oil, and always has a CBD content above 30%. The only thing that separates NatureCBD from being medical marijuana oil is the high CBD content and low THC content (below 0.01%).
It's the Wild West out there. Without any federal regulatory body checking labels, consumers have very little way of knowing what they're buying when they purchase CBD oil. Bonn-Miller co-authored a study that found that 26 percent of CBD products on the market contained less CBD than their label claimed. So the amount you need for an effective dose could vary drastically, not just from product to product, but from bottle to bottle of the same product.
Could cannabidiol help prevent tumors and other cancers before they grow? A 2012 study showed that animals treated with CBD were significantly less likely to develop colon cancer after being induced with carcinogens in a laboratory. Several studies had already shown that THC prevents tumors and reduces them, including one in 1996 on animal models that found that it decreased the incidence of both benign and hepatic adenoma tumors. In 2015, scientists analyzed the medical records of over eighty-four thousand male patients in California and found that those who used cannabis, but not tobacco, had a rate of bladder cancer that was 45 percent below the norm. Topical products can be used to treat and prevent skin cancers. Continuing research is focused on the best ratio of CBD to THC and the most effective dose level in cancer prevention and treatment.
Thanks for your interest in our products. Unfortunately due to strict FDA regulations I am unable to make claims on our products based on your specific needs, I can however share our top selling products in each category. Please view the links below:http://cbdoilreview.org/product/elixinol-cbd-oil-extract-x-pen-1000mg/http://cbdoilreview.org/product/endoca-hemp-oil-drops-1500mg/http://cbdoilreview.org/product/elixinol-hemp-oil-drops-regular-300mg/http://cbdoilreview.org/product/elixinol-cbd-hemp-oil-capsules-900mg/https://cbdoilreview.org/product/vape-bright-starter-pack-200-mg/This is also a great link to some pages that you may find helpful https://cbdoilreview.org/cbd-cannabidiol/I hope this helps and if you have any further questions please feel free to reach out to us at [email protected]
Growing up, Joe was plagued with a myriad of health issues such as gut problems, autoimmune issues, chronic fatigue, brain fog, insomnia, and general inflammation. Both conventional and alternative doctors weren’t able to help him, so he decided to fix himself. With lots of health questions and few satisfying answers, Joe decided to read every research paper he could get his hands on and conduct thousands of experiments on his own body in order to fix his health issues. Joe started SelfHacked in late 2013 when he successfully fixed all of his issues, and now it gets millions of readers a month looking to educate themselves about how they can improve their health. Joe is now a thriving author, speaker, and serial entrepreneur, founding SelfDecode & LabTestAnalyzer.
Rick Cannabis Oil was successfully used in curing my Mother Breast 3 months as stated in the dosage information provided by rick Simpson. Once again i want to thank Rick for his wonderful Cannabis Oil, Our family and friends are now very much happier since my mum has been cured by this wonderful cancerous treatment done with Rick Simpson Cannabis oil our family pride has been restore back again with Rick Simpson Cannabis oil What a miracle. My mother is now back alive, strong and healthy this fact was confirmed by our family Dr. you have the right to stop cancer with Rick Simpson cannabis oil medication please email him now and spread the good work of Rick Simpson.
Eventually, Bekkii built up the confidence to leave the psychiatric unit, but still found it "close to impossible to lead a normal life" due to her anxiety. With treatment options narrowing, Bekkii began to research other ways she might be able to counter her anxiety, and stumbled upon a blog written by a woman who was using CBD oil for her mental health problems. Her mum had seen that a local pharmacy stocked CBD oil made by Celtic Wind Crops, and she decided to give it a try.
“THC”—the more-famous, high-inducing compound in cannabis—“works directly on the cannabinoid system, meaning it attaches to receptors and mimics some of our own internal endocannabinoids,” says Igor Grant, a professor and chair of psychiatry at the University of California, San Diego School of Medicine. But CBD’s interaction with the endocannabinoid system is subtler. “Normally, these endocannabinoid-signaling molecules are broken down by enzymes, and one thing CBD does is interfere with the actions of those enzymes.”
Grant says this may lead to a “dampening” or mellowing of some neurochemical processes, including those linked to pain. “CBD may also react with other receptors, like those for serotonin, and it may have actions that reduce the inflammatory molecules produced whenever there is tissue damage or bacteria coming in,” he says. “But we really don’t know the mechanisms.”
More than 39 million Americans, aged 18 years or more, suffer from anxiety associated disorders. A variety of medications are available in the market for the treatment of these mental conditions. However, despite being effective in some anxiety sufferers, these drugs often do not elicit a favorable response in many generalized anxiety and health anxiety sufferers.
The good news is that most of the official research done on CBD oil has shown that there are very few negative side effects from using it. However, CBD is not without some side effects. Most notably, in the clinical studies for epilepsy, sedation was one of the more common side effects. Decreased appetite and diarrhea were also seen in some patients. Depending on what other medicines they are taking, certain patients may need to have periodic blood tests to check on liver function.
At first, I was wary. Although I live in Los Angeles, where it seems like there’s a medical marijuana depot on every corner, I’m not one for doing drugs (legal or otherwise). I mean, I don’t even take Advil when I get a headache! But despite the fact that CBD oil is made from hemp, it doesn’t contain THC. THC is the compound responsible for the “high” that comes with ingesting marijuana. In fact, scientific reviews have proven that CBD “does not interfere with several psychomotor and psychological functions,” and is safe to ingest without any side effects. Let me repeat: YOU WILL NOT GET HIGH FROM CBD!
27-year-old Bekkii Spain from Sligo in Ireland told Cosmopolitan UK how taking CBD oil made an invaluable difference to her intense anxiety. She began having regular panic attacks back in 2015 due to an uncontrollable fear of her throat closing up. But with counselling being far in the horizon and prescribed medication failing to work for her, Bekkii's anxiety only worsened, and eventually she was admitted to her local psychiatric hospital.
CBD interacts with the body through the endogenous cannabinoid system (ECS) or endocannabinoid system. First discovered in the late 1980’s, the endocannabinoid system regulates the body’s homeostasis, or general state of balance, impacting such functions as mood, sleep, appetite, hormone regulation, and pain and immune response. Like an acrobat on a highwire, as the environment around us impacts our normal balance, the endocannabinoid system “corrects” by mediating our body’s reaction to keep us level.
You can pretty much consider inflammation to be the freaking bane of our modern, fast-paced, industrialized lifestyles. Of the ten leading causes of mortality in the United States, chronic, low-level inflammation contributes to the pathogenesis of at least seven, specifically heart disease, cancer, chronic lower respiratory disease, stroke, Alzheimer’s disease, diabetes, and nephritis.
Unfortunately, due to strict FDA laws, I am not legally able to say that CBD will help with your husbands specific condition, however I can direct you to some literature to help you better understand what CBD may offer. I have attached links below. As far as strength and dosage goes, tinctures and concentrates are absorbed the fastest since it goes directly into your blood stream; the dosage on these can be measured and controlled. Capsules take a little longer to enter your body since it goes through your digestive tract, these are also measured and controlled. I would recommend reading through our page on dosing as well to get a better understanding.https://cbdoilreview.org/cbd-cannabidiol/https://cbdoilreview.org/cbd-cannabidiol/cbd-dosage/I hope these help :)
CBD oil contains CBD (and often other active compounds) in a carrier oil. There are a number of forms of CBD oil, including softgel capsules, tinctures, and under-the-tongue sprays. Some forms of CBD oil can also be applied directly to the skin, in the form of products like creams and salves. The concentration of CBD varies from product to product.
CBD in proper dosages gives nearly the same pain reduction compared to opioid prescription drugs, such as morphine, hydrocodone, and oxycodone, and when combined with these drugs, allows you to use far less of the actual prescription, thus reducing the toxic load on your liver and kidneys. And of course, as you already know, these benefits come without the proven addictive or unsafe nature of opioid drugs.
i have many ailments that has resulted in disability and i am only 46 thus have little quality of life and i loath taking pills!! i take as few prescriptions as possible so relief is low and so low activity is how i manage – though i know isn’t healthy either – but i believe the more prescriptions you take the more sickness will be created. short of stem cell treatment (which hasn’t been developed as far as i know for my issues) CBD is giving me hope.
CBD oil alleviates physical pain and anxiety – both of which can have a negative impact on sleep. Additionally, CBD oil can actually prolong sleep for some, leading to more rest from night to night. Most medical experts agree that marijuana is not particularly beneficial for individuals with medical conditions and/or mental health disorders, as the THC can increase their symptoms; this makes CBD oil a good alternative option for people with the following sleep disorders and medical conditions.
For immediate medicinal effects, vaporizing or smoking work well. This can be helpful for either initial sleep onset or for wakefulness in the middle of a rest period but only lasts one to three hours. The medication effect is immediate, whereas most ingested products take thirty to sixty minutes before taking effect (faster on an empty stomach) and last six to eight hours. Vaporizers that use a cartridge filled with the CO2 concentrate are convenient and highly effective, and these are available in various ratios of CBD to THC. Herbal vaporizers that use the whole plant are also an effective delivery method. Sublingual sprays or tinctures taken as liquid drops also take effect quickly and last longer than inhaled products.
A 2011 study aimed to compare the effects of a simulation public speaking test on healthy control patients and treatment-native patients with social anxiety disorder. A total of 24 never-treated patients with social anxiety disorder were given either CBD or placebo 1.5 hours before the test. Researchers found that pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alertness in anticipation of their speech. The placebo group presented higher anxiety, cognitive impairment and discomfort. (8)
After fighting the effects of thyroid cancerfor 12 years I wanted to die. Every day. Now, please understand that these were thoughts with no actions, I was just miserable in pain.After 1 week on the CBD oil, (5 drops under the toungue 2x per day) I am a different woman. I now have hope. Some of my emotional pain is presenting as physical pain, but IT'S LEAVING MY BODY.
CBD is short for cannabidiol, a cannabinoid compound that is found in hemp and marijuana. Both hemp and marijuana are part of the plant family known as Cannabis. The main difference between marijuana and hemp is the level of THC in each. THC, like CBD, is a cannabinoid compound. There are 60 different known cannabinoids, but THC is the most well-known—the Beyoncé of cannabinoids, if you will. The reason THC is so famous is because it's associated with the psychoactive high that people experience after smoking or ingesting weed.
Intoxicating– Meaning that a substance is habit forming, and can cause you to lose control of yourself. Almost all illegal drugs are considered intoxicating, although at a global scale alcohol is considered to be the most intoxicating of all drugs. Intoxication can take place by directly affecting the brain (psychoactive) or by damaging your body (through toxicity, hence the term).
CBD oil has been shown to be a promising alternative therapy, with the same properties as antidepressants and anxiolytics, but without the numerous risks. Studies show that anxiety can be significantly reduced by CBD. In fact, CBD oil works faster than most anti-anxiety medications. For those who struggle with situational anxiety and panic attacks, this quick response-time can be life-changing.
Canabidol™ Oral Capsules deliver 100% Cannabis Sativa L. from specifically bred industrial hemp plants containing high potency Cannabidiol. Each CBD capsule contains all the Cannabinoids, terpenoids, essential oils and all the other compounds of the cannabis plant. A packet of 30 capsules contains 15,000mg of Cannabis Sativa L. and 300mg of CBD (Cannabidiol) Each capsule contains 500mg of Cannabis Sativa L. and 10mg of the active ingredient CBD
Representations regarding the efficacy and safety of CBDPure have not been evaluated by the Food and Drug Administration. The FDA only evaluates foods and drugs, not supplements like these products. These products are not intended to diagnose, prevent, treat, or cure any disease. Click here and here to find evidence of a test, analysis, research, or study describing the benefits, performance or efficacy of CBD Oil based on the expertise of relevant professionals.
Cannabidiol can be taken into the body in multiple different ways, including by inhalation of cannabis smoke or vapor, as an aerosol spray into the cheek, and by mouth. It may be supplied as an oil containing only CBD as the active ingredient (no added THC or terpenes), a full-plant CBD-dominant hemp extract oil, capsules, dried cannabis, or as a prescription liquid solution.
Based on logical examinations on the subject, in 2011 a gathering of specialists directed an investigation that reformed the considerations about CBD and anxiety. They took ten individuals with social anxiety who had never had any treatment for this issue and separated them into two gatherings. One gathering was given 400mg of CBD and the other fake treatment. The outcomes demonstrated that the individuals who had gotten the CBD oil had effectively enhanced their anxiety side effects contrasted with the phony treatment.
Hi Sarah, I would like to chime in here if I could. I’m not trying to step on Ben’s toes, but we have a K-9 CBD oil that would work great for your Border Collie (my dad has a Border Collie too, great dogs). If you read this, you can visit our website at savinggracecbd.com. Please use coupon code JS410, to receive 10% off. You can feel free to contact me as well, email@example.com.
Another concern is about medications with which CBD might interact. This won’t be an issue with most drugs, says Sunil Kumar Aggarwal, M.D., Ph.D., a palliative medicine physician and scientist who studies cannabis and integrates it into his Seattle medical practice. The exceptions are blood thinners, IV antibiotics, and other drugs whose exact dosing is crucial and must be monitored closely, he says. (Of course, if you have a health problem, talk to your doctor before using CBD, and never take it instead of seeing your physician for a serious condition.)
"As far as I know, CBDs are compatible. My daughter was on several epileptic meds while using MMJ and CBDs. Also as you know CBDs often help with Type 2 diabetes, but not so much with Type 1. However you should continue to monitor closely. My numbers have dropped a little since using CBD. As far as adding CBD to your routine, as always, start slow and build."
 M. H. N. Chagas, A. L. Eckeli, A. W. Zuardi, M. A. Pena-Pereira, M. A. Sobreira-Neto, E. T. Sobreira, M. R. Camilo, M. M. Bergamaschi, C. H. Schenck, J. E. C. Hallak, V. Tumas, and J. A. S. Crippa, “Cannabidiol Can Improve Complex Sleep-Related Behaviours Associated with Rapid Eye Movement Sleep Behaviour Disorder in Parkinson’s Disease Patients: A Case Series,” Journal of Clinical Pharmacy and Therapeutics 39 (2014): 564–566. doi:10.1111/jcpt.12179.
As noted, CBD has been found to have a bell-shaped response curve, with higher doses being ineffective. This may reflect activation of TRPV1 receptors at higher dose, as blockade of TRPV1 receptors in the DPAG rendered a previously ineffective high dose of CBD as anxiolytic in the EPM . Given TRPV1 receptors have anxiogenic effects, this may indicate that at higher doses, CBD’s interaction with TRPV1 receptors to some extent impedes anxiolytic actions, although was notably not sufficient to produce anxiogenic effects.
The dosages mentioned do not take into account the strength of the tincture. I have Elixinol 300, I took 1/2 dropper (0.5ml, which offers 5mg of CBD) as indicated on the bottle and felt severely nauseous for 3 hours thereafter. There is no way I cold take this dose twice per day, as recommended on the bottle. The high dosages on this site must surely be for much weaker concentrations?
Your body is composed of over 60% water, and this means that you’re going to either A) need to take way, way more of a non water-soluble CBD product if you actually want to feel the effects or B) smoke or vape your CBD, which is logistically annoying and not something your kid or your pet can do (and yes, both kids and pets can enormously benefit from CBD usage).
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Did you get an answer for this? I have the exact same scenario. I'm treating my TN with Tegretol, and recently tried CBD. I think I took too much and there are some weird drug interactions with Tegretol and I felt quite stoned....was alone and talking to myself in my head thinking I was Einstein. It freaked me out a bit but I think I took too much. I'm trying lower doses again as recently my TN seems to be resisting the meds, although I have had a lot of emotional stress, which seems to be a trigger. Thanks!! Anna
I have several questions regarding this matter. The first one is where I can order the oil. The second question is which dosage I must start with and the third is how long I must take the CBD oil? Does it help only until I take it or cure depression? Is it true that you can use CBD oil for cooking and that it has many more benefits besides these two?
If CBD-dominant products alone are not enough to treat a particular case, products with a higher ratio of THC are sometimes recommended to better manage pain. For day use, more stimulating, sativa varieties with higher concentrations of myrcene could be added to the formula. In general, for pain, and especially for evening and nighttime, indica strains are favored for their relaxing, sedative effect. A person without experience with THC should use caution and titrate slowly up to higher doses. Research as well as patient feedback have indicated that, in general, a ratio of 4:1 CBD:THC is the most effective for both neuropathic and inflammatory pain. Each individual is different, however—for some, a 1:1 ratio of CBD:THC can be more effective, and others prefer a high-THC strain when it can be tolerated. Each patient’s tolerance and sensitivity will differ, and through titration the correct strain and ratio combination can be found.
Most people do not associate cognitive health issues like anxiety, depression, brain fog, ADD, ADHD, and autism with inflammation, but it turns out that is exactly what the research is finding. There is actually a whole field of research known as the cytokine model of cognitive function studying how inflammation messes with our brains and may cause anxiety disorders. One finding is that elevated levels of NF kappa B (NFkB), an inflammatory bad guy, is associated with anxiety while people with lower levels of NFkB often have lower rates of anxiety.
Dr. Robert Carson is a pediatric neurologist at Vanderbilt University who has evaluated the effectiveness of CBD supplements in kids with seizures. He says the supplements can be beneficial for these children. However, he says, if the FDA follows its advisory panel's advice and approves a pharmaceutical-grade CBD drug, that would open up a new treatment option by delivering a high-quality, consistent dose of CBD.
At Charlotte's Web, we stand behind our products 100%. We work hard to ensure that our quality is second to none, and thousands of our customers agree that this difference is something you will experience. We’re so convinced our products will make a difference you can actually feel, that if any product doesn’t meet your expectations, we want you to send it back within the first 30 days of delivery and we will happily give you the opportunity to exchange for another product or receive a full refund.
I just read your comment on Mary Vance’s website and had to reread the study. It turns out that you are correct. The wording is misleading and I am so disappointed because I wanted to believe. I just purchased some CBD oil for my high cortisol levels. I can’t believe that people are quoting this study when it states the exact opposite. Thank you for pointing that out.
Anxiety disorders are far more serious and can prevent you from maintaining a normal life. Some have said that anxiety is not a disease or illness, but rather a physiological, psychological-emotional state that occurs when we behave apprehensively. It turns into a disorder when the worry and the anxiety it creates interfere with your lifestyle. Ongoing anxiety can lead to numerous medical illnesses and even mental issues, if not dealt with.
The studies done on CBD oil have a pretty wide dose range (anywhere from a few milligrams to hundreds of milligrams). I suggest starting at the lower end (around 10 milligrams) and slowly increasing over a few weeks or months to see what works for you. Some people also do well with splitting the dosage throughout the day instead of taking the dose all at once. As with everything, it is always a good idea to talk with your prescribing doctor if you are on any medications. CBD is generally very safe, but there are some pharmaceutical medications CBD oil could potentially interact with and increase or decrease the pharmaceutical drugs' effectiveness.
Inhibited liver function: The liver regulates the way different drugs are metabolized within the body; this process is known as hepatic drug metabolism. Higher-than-average doses of CBD oil can slow the hepatic drug metabolism process. As a result, users may not be able to process other drugs as quickly. This is particularly concerning for CBD oil users who also take prescription medications.
CBD oil stands for cannabidiol or better known as Hemp oil. Yes, this oil comes from the cannabis plant, therefore the name. Its secret is in the chemicals known as cannabinoids. There are a lot of them and it is known that they have the ability to react with certain brain receptors and other ones located through the body. CBDs popularity has grown in recent years as it offers a calming and soothing effect on users with few or no side effects.
In a 2011 study, scientists wanted to study the effects of CBD on people with SAD. The scientists selected 24 people with this condition who had never received treatment for SAD then divided participants into two groups. One group received 600 mg of CBD while the control group received a placebo. The scientists then asked study participants to take part in a simulated public speaking test while researchers measured blood pressure, heart rate and other measurements of physiological and psychological stress.
But when it comes to pain management, one of the primary uses for CBD oil, deaths from drug overdoses and drug poisoning continue to rise. Deaths from opioid analgesics – one of the most universally prescribed pain management drugs – increased from 4,030 in 1999 to 15,597 in 2009 and 16,651 in 2010. In 2010, 60 percent of all drug overdose deaths (22,134) involved pharmaceutical drugs, and opioid analgesics showed up in about 3 of every 4 of those pharmaceutical overdose deaths. That confirms the predominant role that research has shown opioid analgesics to play in drug-related mortality. Opioids are nasty, brutal drugs with side effects nearly as bad as the conditions they’re taken for, and although deaths from opioids are common, they’re still one of the most turned to bandaids in modern medicine.
The oral use of cannabis and CBD for anxiety appears in a Vedic text dated around 2000 BCE, and it is one of the most common uses of the plant across various cultures. While THC can increase anxiety in some patients, it lowers it in others. However, CBD effects have been shown to consistently reduce anxiety when present in higher concentrations in the cannabis plant. On its own, CBD has been shown in a number of animal and human studies to lessen anxiety. The stress-reducing effect appears to be related to activity in both the limbic and paralimbic brain areas.
I decided to try CBD when I was withdrawing from Tramadol, a synthetic opiate I had been taking for pain (with 2 other medications) for over a year. As I began slowly reducing my use, I experienced a lot of anxiety and muscle tremors in my legs especially. I know that using a marijuana medication meant that my pain doctor would not prescribe for me again, but I was getting off the pain medications one by one anyway, so I don't care.
When pain is localized, topical products can be applied. These can be made using CBD-dominant cannabis as well as THC strains. Topicals affect the cells near application and through several layers of tissue but do not cross the blood-brain barrier and are, therefore, not psychoactive. These may be available as CBD oils, ointments, salves, or other forms, and with varying ratios of CBD and THC (a ratio of 1:1 is often recommended as ideal for skin application). The skin has the highest amount and concentration of CB2 receptors in the body.
Many of the folks I coach and do consults with have always struggled with a “sensitive gut”, irritable bowel syndrome, bloating, gas, constipation and other signs of gut inflammation, and being able to use CBD to reduce gut inflammation could be a game-changer for these people. But from the joints to neural tissue, CBD has a variety of other natural anti-inflammatory effects. Here is just a smattering of the studies done on cannabidiols and inflammation.
This lack of transparency can be boiled down to a couple reasons that are all intertwined. First, what’s holding everything back is the taboo against cannabis (“marijuana”) that continues to exist in our society. We still hear amazingly exaggerated horror stories of what marijuana can do to us. The Reefer Madness that started back in the 1930s hasn’t gone away. This recent video of Gary Johnson faking a heart attack because of a ludicrous claim against marijuana is just one example.
Zuardi, A. W., Crippa, J. A., Hallak, J. E., Bhattacharyya, S., Atakan, Z., Martin-Santos, R., … & Guimarães, F. S. (2012). A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation [Abstract]. Current Pharmaceutical Design, 18(32), 5,131–5,140. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22716160