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What is CBD?Cannabidiol, or CBD, has been a very hot topic in the news for the past year. CBD is the primary non-intoxicating component of cannabis—both marijuana (where it is present in varying concentrations, by strain) and hemp (where it is the dominant cannabinoid). You find CBD-labeled products in grocery stores, drug stores, health food stores, pet food stores . . . in beverages, in cosmetics, in salves and lotions . . . and sometimes, in my area at least, in hardware stores. CBD is everywhere, and its effects are highly touted for everything from epilepsy (where there is value for specific, rare syndromes), pain (where there is some limited evidence), migraine (not much there yet), opioid addiction (maybe someday? as part of a multi-channel approach?), and curing cancer (please don’t go there).

The pharmacology of CBD is not completely understood, but it does interact with both endocannabinoid receptors and other “para-endocannabinoid” receptors and systems. CBD in fact has a very low affinity for CB receptors but nonetheless has significant CB1- and CB2-related activity, sometimes in interaction with THC. (The complex relationship between THC and CBD will be explored in a future post.) CBD also acts at TRPV1 (pain, temperature sensors) receptors,1 5-HT1A (serotonin) receptors,2 and by amplifying adenosine receptor signaling3 (which plays a role in a wide variety of tissues and organs).4 In “everyday life”—at least as far as the recreational use of cannabis goes—CBD plays an important role in counteracting the intoxicating and unpleasant effects of cannabis5 (think anxiety, rapid heartbeat, hunger, sedation), a property which hopefully will be harnessed to improve the medicinal applications of cannabis and various cannabinoid combinations. CBD alone is a strong anti-inflammatory agent,6 and in complex syndromes such as graft-vs-host disease (GVHD), also shows immunosuppressive properties.7

While CBD can also be synthesized in the lab, it is plentiful around the world in hemp plants. One of the problems with all the “OTC” CBD products mentioned above is that they are of widely varying purity and quality. My colleague Marcel Bonn-Miller recently published a study in which he tested 84 open-market CBD products and found a wide range of CBD concentrations. Of tested products, 26% contained less CBD than labeled, which could negate any potential clinical response, and clearly is decptive.8 Until late 2018, CBD, though known to be non-intoxicating and non-addictive and quite safe, was considered along with THC and all other constituent chemicals of cannabis, to be a Schedule I substance, meaning that in the opinion of regulators, CBD (as part of cannabis) has high abuse potential with no accepted medical use. Medications in this schedule may not be prescribed, dispensed, or administered. Other substances listed as Schedule I include heroin, ecstasy, and gamma hydroxybutyric acid (GHB).9 The entire cannabis plant remains under Schedule I by US federal law.10 What changed in 2018 was the passage of the Farm Act , which for the first time legally separated hemp from marijuana.11 Now there is absolutely NO difference between CBD derived from hemp and CBD derived from marijuana, nor for that matter between either of those and synthetic CBD . . . but at least there seems to be a path forward for broader use (and therefore, hopefully, broader and more rigorous research) of CBD. Unfortunately, all these months later, the DEA has still not given us a clear interpretation or operationalization guidelines of the Farm Bill impact.

What is of particular note is the first-ever approval of a phytocannabinoid (that is, a plant-derived cannabinoid), in this case, CBD, as a pharmaceutical agent by the FDA. The UK’s GW Pharmaceuticals received approval for their tightly controlled, pure CBD for the treatment of a couple of (fortunately) rare and debilitating pediatric seizure syndromes—Lennox-Gastaut and Dravet—that are notoriously unresponsive to conventional anti-seizure treatment. GW Pharma has a number of other cannabinoid treatments in clinical trials.

While CBD does hold promise for the relief of anxiety, insomnia (or at least poor sleep quality), and chronic pain, much research is needed. We don’t know what dose to give, we don’t know whether or not to combine it with other treatments, and we don’t know when to start it. My colleague Yasmin Hurd has recently written about how we might best conduct the necessary studies.12 There is an exciting frontier out there.13 Patient education is vital—“expectation management” is an important aspect of any cannabis/cannabinoid treatment.14,15 There are too many promising (and some, unfortunately, woefully inadequate) studies to cite here, but as attention-worthy studies are published about fulfilling the therapeutic potential of CBD, we’ll discuss them on this site.

Resources

1. Bisogno T, Hanuš L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845-852. doi:10.1038/sj.bjp.0704327
2. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037-1043. doi:10.1007/s11064-005-6978-1
3. (15) (PDF) Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci USA 103: 7895-7900. ResearchGate. https://www.researchgate.net/publication/7109024_Carrier_EJ_Auchampach_JA_Hillard_CJ_Inhibition_of_an_equilibrative_nucleoside_transporter_by_cannabidiol_a_mechanism_of_cannabinoid_immunosuppression_Proc_Natl_Acad_Sci_USA_103_7895-7900. Accessed March 17, 2020.
4. Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V. Adenosine Receptors: Expression, Function and Regulation. Int J Mol Sci. 2014;15(2):2024-2052. doi:10.3390/ijms15022024
5. Russo EB, Marcu J. Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. Adv Pharmacol San Diego Calif. 2017;80:67-134. doi:10.1016/bs.apha.2017.03.004
6. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1(7):1333-1349. doi:10.4155/fmc.09.93
7. Yeshurun M, Shpilberg O, Herscovici C, et al. Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2015;21(10):1770-1775. doi:10.1016/j.bbmt.2015.05.018
8. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA. 2017;318(17):1708-1709. doi:10.1001/jama.2017.11909
9. Gabay M. The Federal Controlled Substances Act: Schedules and Pharmacy Registration. Hosp Pharm. 2013;48(6):473-474. doi:10.1310/hpj4806-473
10. Drug Scheduling. https://www.dea.gov/drug-scheduling. Accessed February 23, 2020.
11. Hudak J. The Farm Bill, hemp legalization and the status of CBD: An explainer. Brookings. December 2018. https://www.brookings.edu/blog/fixgov/2018/12/14/the-farm-bill-hemp-and-cbd-explainer/. Accessed March 17, 2020.
12. Hurd YL. Leading the Next CBD Wave—Safety and Efficacy. JAMA Psychiatry. January 2020. doi:10.1001/jamapsychiatry.2019.4157
13. Sarker SD, Nahar L. Cannabidiol (CBD) – An update. Trends Phytochem Res. 2020;4(1):1-2.
14. Harned RG. CBD: A Resource for Patients. :12.
15. Pratt C. Educating Patients on Cannabidiol (CBD). Fam Med Clerkship Stud Proj. January 2019. https://scholarworks.uvm.edu/fmclerk/500.

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