Editor’s Note: Carrie Corboy is a member of the Critica Advisory Board and wrote this piece in response to a recent Critica commentary about CBD. She is also Senior Director at Janssen R &D, a division of Johnson and Johnson. Carrie Corboy is a licensed pharmacist. Her focus has been in areas of compliance, policy, and development of new medications. Her current projects include a considerable focus on patient engagement. Carrie has a strong personal and professional interest in improving people’s understanding of scientific information.
This article is in response to the 29 July 2019 Critica.life post “To CBD or Not to CBD: Many unanswered questions remain in understanding the health benefits of CBD.” I am concerned that the conclusion of “To CBD…” does not address the history of why cannabis plants were made illegal in the first place (i.e., not for any science-based reason) and dismisses what we do know about the cannabis and the cannabinoids THC and CBD. While I agree there is much more to learn, research has revealed important information about the compounds found in the cannabis plant and this knowledge should be applied by health care professionals for the benefit and protection of patients.
While humans have been using cannabis for thousands of years, it has been for medical reasons as well as ‘getting high.’ Fast forward to recent US history, many people might be surprised to learn that cannabis was prescribed by doctors and appeared in the United States Pharmacopeia from 1850 until 1942. Why was it pulled from the USP? Due to political forces—sometimes tied to the paper industry for which hemp is a competitor to wood, and unabashedly tied to racism (Harry Anslinger, head of the Federal Bureau of Narcotics, is quoted as saying “Reefer makes darkies think they’re as good as white men” and “…the primary reason to outlaw marijuana is its effect on the degenerate races.”) The term ‘marihuana’ itself is slang for the cannabis plant. Why is this important? Because cannabis was removed from the national compendium and, between the years of 1937 with the Marijuana Tax Act and 1970 Controlled Substances Act, became prohibited from medical or other use for no scientific reason. Not only did this end access, it significantly curtailed research for many years. Even today, research is restricted to product from one government-owned farm and requires a rigorous process to get that product from that farm for research purposes. Thankfully, this is changing. Despite this reduced access and limit to specific source of cannabis, we have learned a lot to-date.
In 1988, receptors for cannabis compounds were identified in the body. Around 1990 we confirmed the endocannabinoid system, which includes endogenous cannabinoids [examples include anandamide and 2-arachidonoylglycerol (2-AG)] and two receptors for them, CB1 (largely found in the central nervous system) and CB2 (found in peripheral nervous system and immune system). Research has determined that the endocannabinoid system serves to maintain homeostasis; when an imbalance is detected within our internal environment, the body synthesizes endocannabinoids that interact with the cannabinoid receptors.
The most prevalent compound in cannabis is delta-9-tetrahydrocannabinol (THC) and the second most prevalent is cannabidiol (CBD). However, more than 100 cannabinoids have been identified in the plant.
While there are a few FDA approved medications on the market that contain THC or CBD, there are important differences among them and also compared to cannabinoids found in the plant. Marinol and Syndros (dronabinol) are synthetic THC medicines, i.e., they are manufactured in a laboratory and not extracted from plants. They are both DEA Controlled Dangerous Substance  Schedule III. Another THC-product is Cesamet, also synthetic, and is Schedule II. Epidiolex, which is CBD-only and is extracted from plants, is Schedule V, the least restrictive of the DEA’s five scheduled classes of medications with potential abuse potential. Finally, there is a THC/CBD 1:1 ratio product called Sativex (nabiximols) available in more than 25 countries, but not yet in the US (therefore it does not have an assigned DEA CDS Schedule). This approach has a history (find a physiologically active compound in a plant, extract/purify, possibly synthetically synthesize, and market) with the pharmaceutical industry. Digoxin comes to mind as an example. Why is this important? Research has shown that cannabis extracts (cannabinoids) are complementary to each other in their effects on the human body. For example, many people experience anxiety when they use a THC-only product. A THC:CBD product—in, for example, a 1:1 ratio—often results in the benefits of THC without the anxiety. And this ‘working together’ is not limited to cannabinoids, but the other compounds in cannabis called terpenes (the compounds in the plant that we associate with the odors of cannabis) and flavonoids (yes, like in dark chocolate and red wine). You may have heard of terpenes as they are responsible for the smells and flavors of both essential oils and vaped cannabis. This ‘working together’ of compounds in the cannabis plant is referred to as the ‘entourage effect’.
Focusing on CBD, which we know does not convey a “high,” it’s worth clarifying that the laws are a mess, and so there is no simple ‘it is legal’ or ‘it is illegal’ statement that can be made. Even FDA’s Q&A page on the topic is less than direct. There are articles about how states and municipalities are applying certain laws and not others to not just marijuana but CBD-only products. What we can say is the Farm Act of 2018 legalized hemp. The US Government has appropriated the term hemp for legal purposes to mean cannabis that has less than 0.3% THC. Further, relating to prescription CBD (Epidiolex) and supplement CBD, a product can be both a prescription drug and an over-the-counter supplement. It is rare, and the dosage of the formulations can be different, but folic acid is one such example.
So, CBD is the new supplement to the market, and it is everywhere. The same cautions for any other supplement absolutely apply to CBD. It falls to the consumer to identify a product that has undergone Good Manufacturing Practice testing and is not contaminated with things like heavy metals and contains what it says it does. In parallel, the FDA has opened the discussion on the science of cannabinoids while also pursuing companies making claims in the marketing of their CBD products.
The “To CBD” article points out the limited research (true, but now you know why, and there’s a lot more underway), asks whether animal research translates to humans, and notes the possibility of a placebo effect. With regard to the latter, placebo effects may apply to all supplements and even many FDA-approved medications. Epidiolex has on its website: “The precise mechanisms by which EPIDIOLEX exerts its anticonvulsant effect in humans are unknown. However, EPIDIOLEX does not appear to exert its anticonvulsant effects through interaction with cannabinoid receptors.” In fact, I would argue that the research efforts across the country are broad and deep and we actually do know a lot of important information about cannabinoids (how it is metabolized and, therefore, medications it is likely to interact with, its relative safety compared to other medicines used for pain, the effect of food on its absorption, its presence in breast milk, the risk for bringing forward schizophrenia in young people with a family history, etc.); this is information that health care professionals should be using to assess cannabinoid use for their patients and counsel them on that assessment.
We heard recently from the FDA that pregnant women and people under 25 should not partake in cannabis. Considering pregnant women shun even caffeine, and we don’t know how cannabis might affect the unborn, this is really no surprise. The age guideline is coming out of science, where those in the research space do suggest 25 is the age under which cannabis use should be avoided, especially for the psychiatric reasons.
Why are patients eager to try CBD? Well, I would argue that it’s new and most people probably know someone that has experienced ‘marijuana’ such that there’s a feeling of safety in its use. No one has ever died of an overdose of marijuana and while that’s a very low bar for safety, it’s a much better statistic than many prescription drugs taken according to their labeling and certainly a much better statistic than alcohol, which many people use to ‘self-medicate’ with, despite serious, publicly-known risks.
The point I’d most like to make is that instead of concluding with “No one can responsibly recommend that a person use CBD to treat any serious health condition” I would put forth the following: “In trying to help patients, health care practitioners should not limit their scope to prescribed medication or other Western Medicine modalities, as many patients may benefit from integrating other treatments. No different than acupuncture, other supplements, essential oils or massage therapy, CBD (and cannabis) should be considered by the health care practitioner according to State law (in order not to make recommendations that put the patient at legal risk). An educated health care professional can, and should, make recommendations based on the patient’s co-morbidities, age, needs, concerns, conditions, treatment successes and failures, and quality of available product. I am excited by the research going into cannabis, including CBD, and can only hope that other integrative therapies get similar levels of attention.
In summary, my disagreement with the original article lies in the lack of background on the therapeutic use of cannabis before it was made illegal and why it was made illegal, and the important scientific knowledge we have today, which is enough to guide or dissuade use in certain people. The suggestion that that the use of cannabis, and specifically CBD, is completely unfounded unless according to package inserts of FDA-approved products has its own potential negative consequence. In my opinion, this conclusion is likely to squash the much-needed patient-pharmacist interaction on this important topic—and keep use underground. This conclusion also lets health professionals off the hook; cannabis is a rapidly evolving space—medically, scientifically and legally—and health professionals—especially pharmacists—need to be involved and educated for the protection and benefit of our patients.
 https://www.leafly.com/news/cannabis-101/cannabis-and-the-constitution-a-brief-history-of-cannabis-in-the-u-s?q=history%20of%20cannabis%20in%20the%20US&cat=article; https://news.medicalmarijuanainc.com/the-road-to-prohibition-why-did-america-make-marijuana-illegal-in-the-first-place/; https://www.scientificamerican.com/article/the-science-behind-the-dea-s-long-war-on-marijuana/
 Potential Adverse Drug Events and Drug-Drug Interactions with Medical and Consumer Cannabidiol (CBD) use; Joshua Brown, Almut Winterstein; Journal of Clinical Medicine; 8 July 2019; J.clin.Med.2019,8,989;doi:10.3390/jcm8070989