Behind the Science: Is CBD Safe?

Video Description

These days, it seems like you can buy CBD just about anywhere…but is CBD safe? Is it addictive? What are the FDA’s concerns?

 

Video Transcript

Dr. Jamie Corroon
My name is Dr. Jamie Corroon. I'm the medical director at the Center for Medical Cannabis Education in San Diego California. In this video, I'd like to talk about the safety of CBD. Before I do, I should disclose that I consult for a variety of manufacturers of cannabis products, and that I'm on the Medical Advisory Board of CV Sciences, a leading manufacturer of hemp derived CBD products. I'm going to attempt to answer the following questions. How are consumers using CBD products? What concerns does FDA have? How does the dose of CBD in a prescription medication differ from the dose or the serving size of CBD in a dietary supplement? Have toxicologists reviewed safety data on these products? How common is an adverse reaction or an adverse event to + CBD oil products? And finally, is CBD addictive?
I manage a medical cannabis oriented clinical practice in San Diego California. I've been providing this type of specialty care for over three years now. About two years ago my clinical practice changed: my patient population shifted from a majority of very sick patients using THC dominant products, to a majority of mild to moderately sick patients using CBD dominant products. A few different phenomena led to this shift, foremost among them was the emergence of CBD, which has taken the world by storm. I credit Sanjay Gupta's CNN special report entitled “weed” for launching the CBD craze. The first episode told the story of Charlotte Figi, a child with a severe seizure disorder who benefited greatly by using CBD oil to control her seizures. Her story went viral, and CBD flashed on the radar of many families in similar circumstances. Within the year, nine states with no medical marijuana program enacted limited laws that allowed the use of CBD products for treating seizure disorders. Unfortunately, Charlotte Figi passed away in April of 2020. Her legacy will not be forgotten however. Patients started scheduling appointments with me specifically to use CBD. They were highly curious but also confused, and they still are. What is the effective dose? How do I find a high quality product? What is the risk of a drug interaction between CBD and a hemp derived product and my other medications? These are all important questions that are best answered by a knowledgeable health care professional.
I'd like to start with the most important concept in toxicology. The Swiss German physician Paracelsus is frequently credited with this concept plainly stated “the amount of a substance is the critical factor in determining its safety.” The duration of exposure is also important, but as the saying goes the dose makes the poison. For example, drinking water is universally considered a safe activity, assuming the water isn't contaminated with something. But drinking too much water can actually kill you. Water intoxication can be fatal, so whenever we're evaluating the safety of some substance, we have to be thinking about the dose. I conducted a cross-sectional study with some co-investigators that was published in 2018. We looked at CBD usage patterns, or how people were using CBD products. Among other things, approximately 62% of more than 2,400 participants reported that they used CBD products to treat a medical condition or a symptom of a medical condition, despite the fact that these products are not FDA approved for that purpose. The most frequently reported conditions were pain, arthritis, anxiety, depression, sleep disorders, migraines and many others. And they reported that CBD products were effective, 2/3 reported that they worked moderately well or very well by themselves. Most reported learning about CBD from friends, family members, and Google as opposed to health care professionals. And about a third reported experiencing non serious adverse effects like sedation, gastrointestinal discomfort, loose stool etc. We would have asked them what dose they were taking, but it was pointless because nobody knows, nobody knows how much CBD they're taking. At least one reason for this is because many manufacturers have emitted that information from their label. Often they'll put the amount of CBD in the entire bottle on the front, but they won't put the amount per serving on the back, perhaps this is in hopes of staying out of FDA crosshairs. While the FDA recognizes the significant public interest in hemp and hemp derived compounds, particularly CBD, it thinks there are many unanswered questions about the science, the composition of these products, as well as their safety and quality. The FDA says that they're concerned about the safety of CBD products, specifically as it pertains to liver toxicity, drug interactions, and reproductive toxicity. To be fair, CBD is relatively new and we don't know if it is safe to take over a long period of time. The FDA is also not convinced that certain vulnerable populations, like children and pregnant and breastfeeding women, should be taking these products. Product contamination is another issue, what is actually in these products, and do they contain the amount of CBD that is listed on the label. Some studies have demonstrated that they do not, yet the FDA has already approved a prescription form of CBD called EPIDIOLEX, which is approximately 98 or 99 percent CBD. So how can they be concerned about the safety of CBD when they have already approved CBD as a drug? The concerns the FDA has are more about the dietary supplement version of these products because these products are extracts that are generally not highly purified, and as a result contain tens or even hundreds of other compounds besides CBD. Here's the EPIDIOLEX drug monograph. It warns of elevations of transaminases, which are liver enzymes, and it says the risk may be greater at higher doses. And among those taking CBD and valproate, an antiepileptic drug, I presume that these three clinical trials were part of the new drug application submitted to the FDA for approval of EPIDIOLEX. 5 to 20% of the research participants in these trials exhibited increases in liver enzymes after chronic administration of 20 milligrams per kilogram. These elevations resolved after discontinuing epidemics. These participants were taking a median number of three other anticonvulsants in addition to EPIDIOLEX. Some were taking significantly more, as well as an unknown number of other medications. It's important to note that much of what we know about the safety of CBD comes from these studies, and studies like them, which use high doses of highly purified CBD in pediatric patients with severe seizure disorders, who are also taking multiple other medications concurrently. The elevation and liver enzymes may be more likely to be due to drug interactions than to any intrinsic toxicity of CBD. Here is the maximum recommended maintenance dose of EPIDIOLEX. 20 milligrams per kilogram per day. 20 milligrams per kilogram per day, for the average female in the United States is 1,550 milligrams of CBD per day. That's a lot of CBD. In fact, that's more CBD than you'll find in the vast majority of hemp derived products available today. Here are the three most highly concentrated CBD products offered by three leading brands. The maximum recommended daily dose of EPIDIOLEX contains more CBD than in an entire two ounce bottle of CV Sciences most concentrated PlusCBD oil Product. Looked at another way, if you compare a serving size of a hemp derived CBD product to a dose of prescription EPIDIOLEX, you can see that 1 15 milligram Plus CBD Oil softgel represents less than 4 percent of the recommended starting dose, and less than 1 percent of the maximum recommended maintenance dose of EPIDIOLEX. That's two orders of magnitude lower when compared to the maximum daily maintenance dose. 
Many, but not all of these products state on their labels that they are not intended for individuals under 18 years of age or women who are pregnant and breastfeeding. Some have been deemed safe enough to put in the food supply, according to panels of independent toxicologists. To their credit, CV Sciences was the first company to publish toxicological studies in a peer-reviewed journal, and obtained GRAS self-affirmation for a hemp extract in September 2018. GRAS stands for: Generally Recognized As Safe, and it's a fairly high standard for demonstrating safety. In December 2018, Manitoba Harvest announced that the FDA had acknowledged their GRAS self-affirmation for some food products, namely hulled hemp seeds, hemp seed protein, and hemp seed oil, which is not CBD oil. Hemp oil is made from the seeds,  CBD oil is made from the flowering tops of the plant. If these food products do contain any CBD, it's only in trace amounts, and most likely due to contamination during processing. My understanding is that Manitoba Harvest used the CV Sciences toxicology work as part of their GRAS dossier, and received self-affirmation for their hemp extract in May of 2019. So if you're keeping score at home, that's one FDA-approved drug to self affirmed GRAS certified hemp extracts, and three FDA GRAS certified hemp food products. 
Post-marketing surveillance is one way the dietary supplement manufacturers can monitor the safety of their products. In summer 2020, CV Sciences published post market surveillance data for two years: 2018 and 2019. They recorded 1151 customers had reported an adverse event over that two-year period. Only 2 adverse events were classified as serious. The total number of adverse events reported was 1429. This represents a small fraction of the roughly 5 million products that were sold during that period of time. The most common adverse events were abdominal discomfort, hypersensitivity reactions, and headaches. 
This article on Forbes.com got a lot of attention last summer: Marijuana Study Finds CBD Can Cause Liver Damage. It references a preclinical study conducted at the University of Arkansas that was published earlier that year. Project CBD, a California-based nonprofit CBD advocacy publication, quickly responded with an article that attempted to discredit the study. My opinion is that the Forbes article was over generalizing the research, and directly applying the findings of an animal study to humans. I think the authors of the study were doing good science, but they were using very high doses of CBD in an extract, and they were attributing the effects to one molecule in that extract, which is CBD. We'll talk more about that. The authors concluded that their study raises some serious concerns about the safety of CBD. These mice were force-fed a cannabis extract that was only 25% CBD, yet their conclusions about the hepatotoxicity were specific to CBD, as opposed to the extract itself, which is comprised of a multitude of other constituents. In fact, 75% of the extract was comprised of constituents other than CBD. So if this extract led to toxicity at given doses, how do we know it was the CBD? Also not all extracts are the same, so if this extract resulted in toxicity, does that necessarily mean that some other extract, that has a different chemical profile, would also lead to the same toxicity? Maybe not. Not all CBD products are the same, there are differences between highly purified isolated CBD products, and full-spectrum extract products. There are differences between full-spectrum extract products themselves, and differences between finished products, the form factor, and many other things. The safety and efficacy profiles of these various products may be different in very important ways. For acute toxicity over 24 hours, the lowest dose, 246 milligrams per kilogram, was equal to the maximum daily dose of EPIDIOLEX., so this is adjusted from a human to a mouse. For sub-acute toxicity over 10 days, the lowest dose was 61.5 milligrams per kilogram, which is equal to the recommended starting daily dose of EPIDIOLEX. The higher doses are 3x and 10x the starting dose of EPIDIOLEX. The authors state that there were elevations in hepatic toxicity parameters, including elevations in liver enzymes in mice fed ten times the maximum maintenance dose of EPIDIOLEX. The same was true for the sub-acute phase for the 615 milligram per kilogram dose, which is ten times the starting dose of EPIDIOLEX. They found similar outcomes, but they were not statistically significant to be clear. No hepatic toxicity was seen in the recommended doses of EPIDIOLEX.
 In 2015, Nora Volkow, the director of the National Institute of Drug Abuse, testified in front of the Senate caucus on International Narcotics Control. She stated that after a review of 25 Studies on the safety and efficacy of CBD, they did not identify significant side effects across a wide range of doses, including acute and chronic dose regimens. In a 2017 editorial, dr. Volkow wrote in short, CBD appears to be a safe drug with no addictive effects. And finally, the leading health organization in the world, the World Health Organization has determined that CBD is generally well tolerated and has a good safety profile, per their 2018 critical review report. In summary, the dose makes the poison. Safety of a substance cannot be ascertained without defining the dose, as well as the duration of exposure. The FDA has determined that high doses of CBD are safe and effective for treating certain seizure disorders in pediatric patients. The FDA has questions about the safety of non-FDA-approved hemp derived products, however. The difference in prescription medication dosing in EPIDIOLEX is very different than the serving size found in a dietary supplement. Some hemp extracts have already been deemed safe at certain dosages by panels of independent toxicologists. Adverse event rates are very low for PlusCBD Oil products. And finally, the director of NIDA, the National Institute of Drug Abuse and a committee within the World Health Organization have stated that CBD is not addictive. 
This video is not intended to be a systematic and comprehensive review of the safety of CBD. With that, I'd like to thank you for your time and your attention if you have any questions please reach out to me