A Cross-Sectional Study of Cannabidiol Users

Cannabidiol (CBD) is one of more than a hundred cannabinoids found in Cannabis sativa L (Cannabis spp. or Cannabis), a plant more well known colloquially as marijuana and hemp. CBD is typically the second most abundant cannabinoid found in Cannabis after tetrahydrocannabinol (THC).¹ CBD was first isolated in 1940 and characterized structurally in 1963.^2,3

CBD is well tolerated in humans and maintains a good safety profile.^4,5 Neither abuse nor dependence has been demonstrated.⁵ In preclinical studies, CBD shows potential therapeutic efficacy against a diverse assortment of medical conditions. These include seizure disorders, psychotic symptoms, anxiety, depression, inflammation, cancer, cardiovascular diseases, neurodegeneration, symptoms of multiple sclerosis, and chronic pain, either used alone or when coadministered with THC.^5–20

In October of 2017, a New Drug Application was submitted to the U.S. Food and Drug Administration (FDA) to seek approval of CBD isolated from marijuana for the treatment of two pediatric seizure disorders. Approval was granted in June, 2018, making Epidiolex (cannabidiol) the first plant-derived Cannabis compound approved as a drug by the FDA. Availability of Epidiolex is pending Drug Enforcement Administration (DEA) rescheduling of cannabidiol, which is expected to occur within 90 days.^21–23 Sativex (nabiximols), a combination drug with equal parts CBD and THC extracted from marijuana, is currently approved to treat spasticity due to multiple sclerosis in >30 countries worldwide but is not approved in the United States.^17,21

The worldwide regulatory status of CBD is complex and constantly changing.⁵ While CBD is legal in many countries as a component of prescription Sativex (nabiximols), it may be simultaneously illegal as a component of a nonapproved Cannabis extract containing >0.2% (particularly in European countries) or 0.3% THC. In Europe, individual European Union Member States currently determine the legality of CBD within their borders. Most allow prescription CBD products, as do Australia and New Zealand.^5,24 Canada became the second nation in the world to legalize Cannabis for recreational use in June 2018.²⁵ The World Health Organization's Expert Committee on Drug Dependence recommended that CBD should not be controlled by Schedule I of the 1961 UN Single Convention on Narcotic Drugs.⁵ Their comprehensive report is expected this year.

In the United States, until such time as it is rescheduled, CBD from marijuana is deemed by the DEA to fall within the purview of the “marihuana extract rule” (Rule). A dispute over the scope of the Rule was litigated in federal court. The Court found that the Rule applies to extracts of marijuana but that the industrial hemp provisions of the 2014 Farm Act (i.e., “The 2014 Farm Bill”) preempt the Controlled Substances Act (CSA), which the DEA enforces.²⁶ Thus, hemp cultivated in compliance with the Farm Bill is not a controlled substance. The Court did not address the issue of CBD directly, however, and left open the issue of the legal status of CBD derived from industrial hemp, from imported “nonpsychoactive hemp” or from parts of the Cannabis sativa plant excluded from the legal definition of marijuana in the Controlled Substances Act of 1970.^27–35 Despite conflicting legal interpretations, and DEA prohibition, hemp-derived CBD products can currently be purchased as dietary supplements both online and over the counter throughout most of the country. To complicate matters further, the FDA does not recognize CBD as a dietary supplement ingredient because of its status as an Investigational New Drug.³⁶

This regulatory confusion has not deterred consumers from exploring the purported benefits of CBD. Retail sales of hemp-derived CBD products in the United States reached $170 million in 2016, and are projected to grow at a 55% compound annual growth rate over the next 5 years to reach >$1 billion. These estimates do not include marijuana-derived CBD.³⁷ Although Cannabis users have been extensively studied data characterizing the individual use of CBD are scarce. The goal of this study was to collect survey data to elucidate how, and why, individuals are using CBD.

To our knowledge, this is the first published survey (aside from industry reports) that specifically analyzes CBD users, as opposed to overall Cannabis or medical Cannabis users. The results of this study suggest that CBD is used more frequently as a specific therapy for medical conditions than for general health and well-being. This stands in contrast to the majority of marijuana users, who largely use THC-dominant Cannabis for recreational or nonmedical reasons.³⁸

The most common medical condition for which CBD was reportedly used was pain. In preclinical studies, CBD-based analgesia is associated with potent immune-modulatory, anti-inflammatory, and antioxidant activity.^39–47 CBD acts as an agonist for a wide variety of cell-surface receptors including adenosine A2_A, 5-HT_1A, TRPV1, α7nAch, α3 glycine receptors, and the peroxisome proliferator-activated receptor gamma (PPAR-γ) nuclear receptor. These receptors are all associated with anti-inflammatory activity.^48–58 Consistent with the efficacy reported by survey respondents, CBD has been shown to reduce inflammatory cytokines in murine models of inflammatory disease and chronic and acute pain.⁵⁹

The endocannabinoid system may also play a role in CBD-mediated analgesia. CBD inhibits enzymes (i.e., fatty acid amide hydrolase and monoacylglycerol lipase) that degrade endocannabinoids. This inhibition is associated with increased endocannabinoid levels, analgesia, and opioid-sparing effects in preclinical models of pain.⁶⁰

Anxiety and depression were also commonly reported reasons for CBD use in this survey. CBD has long been proposed to inhibit THC-associated anxiety by antagonizing cannabinoid receptor activation by THC.^61–63 CBD may also reduce anxiety via the serotonin 5-HT_1A and/or GABA_A receptors.^14,64 These receptor pathways are being explored in hopes of novel therapeutic strategies for phobias, post-traumatic stress disorder, and drug abuse.^65,66

The majority of survey respondents learned about CBD from internet research, family members, or friends. This was the case for both medical and general health and well-being users. Over 74% of respondents reported using CBD daily or more than daily. Sublingual delivery was the most common route of administration in both groups. The frequency of use of sublingual preparations found in this study contradicts a recent industry-funded CBD survey where respondents reported more frequent vaping, smoking, and topical use.⁶⁷ This industry survey was collected from customers of an online medical marijuana recommendation service. Presumably, these respondents were seeking marijuana-derived products, so the frequency of inhalation as a method of administration is consistent with marijuana users overall.⁶⁸ Our finding may be in part due to the fact that hemp-derived CBD products are largely distributed online and in health-food stores and widely offered as oral preparations.

The percentage of respondents (55.17%) who reported regular Cannabis use is markedly higher than national estimates. In 2015, an estimated 8.3% (∼22.2 million people) of individuals aged 12 years or older had used marijuana in the past month.⁶⁹ The reason for the higher rate of Cannabis use among survey respondents is not clear, although one possibility is that Cannabis users would be more likely to have heard of CBD. However, CBD use by a relatively high percentage (44.83%) of nonregular Cannabis users suggests that individuals are not using CBD as a perceived legal route to THC consumption.

Approximately half of all respondents reported using CBD for <1 year. Just over 10% reported using CBD for >5 years. Nonserious adverse effects were relatively common among respondents and higher among those using CBD for general health and well-being, despite the fact that this group reported less frequent use than medical users. While dry mouth, sedation/fatigue, decreased appetite, and diarrhea have previously been reported following CBD use,^6,7 other studies have demonstrated no adverse effects.^10,70–72 This dichotomy may be related to dose, interactions with prescription medications, or both. More broadly, adverse effects may also be related to the method of administration and/or the use of purified, high-dose CBD as opposed to CBD in a whole plant extract. These questions and more reinforce the need for more research on unanticipated consequences of CBD use, particularly the impact of long-term usage.^4,5 Many of the adverse effects reported in this study (i.e., euphoria, hunger, and red eyes) are commonly associated with THC use.⁷³ These analyses did not attempt to discriminate between hemp-derived CBD and marijuana-derived CBD products, which may have differing chemical constituents (including THC content) and therefore different effects. Further, no discrimination could be made between isolated CBD and CBD used as a constituent of a whole plant extract.

Industry-originated studies have found that users are confused about the source of their CBD and the concentration of CBD and other ingredients.^67–74 It is worth noting that independent research has confirmed that the CBD content in almost 70% of CBD-labeled products available online may be mislabeled. In one study, 43% of products were underlabeled and 26% were overlabeled for actual CBD content. More than 20% contained detectable levels of THC.⁷⁵ Since CBD-containing products are largely unregulated there is no obvious way for users to know the quantity of CBD, or other constituents, which may be present in the products they use. Given this uncertainty, it is possible that some of the reported efficacy and the adverse effects may be in part due to the inclusion of other compounds in the CBD preparation, including THC.

The use of CBD among individuals for both specific health conditions and general health and well-being is widespread. The results of this study demonstrate that individuals are learning about CBD from the internet, friends, or family members, rather than from healthcare professionals. CBD is being used as a specific therapy for a number of diverse medical conditions—particularly pain and inflammatory disorders, in addition to anxiety, depression, and sleep disorders. A large percentage of respondents indicate that CBD treats their condition(s) effectively in the absence of conventional medicine and with nonserious adverse effects. These data provide a compelling rationale for further research to better understand the therapeutic potential of CBD in treating chronic pain, anxiety, depression, sleep disorders, and other medical conditions.

The authors thank Gina Spidel for help with survey design, proofreading, and assistance with the SDSU Electronic Internal Review Board; Edgar Herrera for setting up the survey Facebook page; Belle Della Cruz for help with survey wording; and Rod Kight, Esq., for assistance in clarifying the regulatory status of CBD in the United States.

Cite this article as: Corroon J, Phillips JA (2018) A cross-sectional study of cannabidiol users, Cannabis and Cannabinoid Research 3:1, 152–161, DOI: 10.1089/can.2018.0006.