Murky Legal Status of Cannabis
As noted, the legal status of cannabis in the United States remains complicated. The 2018 Farm Bill changed the definition of marijuana to exclude hemp and legalized the production and sale of hemp plants and CBD preparations including “isomers, acids, salts, and salts of isomers, with a THC content no more than 0.3% on a dry weight basis.”10 Any products with >0.3% THC, however, remain a Schedule I substance as per Drug Enforcement Administration (DEA) regulation.10
Federal prohibition of cannabis has made consistent procurement of pharmaceutical-grade cannabis products difficult. In August 2019, the DEA distributed a press release outlining its efforts to improve access to cannabis for research. “Over the last 2 years, the total number of individuals registered by DEA to conduct research with marijuana, marijuana extracts, derivatives, and THC has increased by more than 40% from 384 in January 2017 to 542 in January 2019,” noted the agency.11 Similarly, in the last 2 years, the DEA has more than doubled the production quota for marijuana each year based on increased use projections for federally approved research projects.
Federally, CBD has been classified as a medicine, not a supplement.12 This does not equate to legality; instead, it communicates that oversight of CBD has shifted from the DEA to the US Food and Drug Administration (FDA).11 The FDA has determined that CBD is an investigational product and does not fall under the traditionally lax oversight afforded to dietary supplements. While the growth and sale of hemp is now legal, the FDA prohibits the sale and marketing of CBD with any associated health claims. At this time, the FDA has issued warning letters to but has not pursued prosecution of violators.13
Another pitfall of CBD legality is the mislabeling of THC content. Hemp often naturally contains a level of THC that exceeds the legal standard of 0.3%. While most plants are hermaphroditic, cannabis plants are male or female. When cannabis plants reproduce, dormant genes such as those that contribute to THC production may activate. Since pollination and reproduction results in less CBD production, most commercial hemp producers only use female plants to minimize the risk of sexual reproduction. However, hemp grown outside of a greenhouse remains susceptible to male pollen exposure, which can lead to THC production in previously CBD-only female plants.14 A retail CBD product that has not undergone rigorous lab testing may contain more THC than is considered legal (above the 0.3% limit set by the DEA). A recent study found that approximately 70% of CBD products are mislabeled, with many containing THC exceeding the legal standard of 0.3%.15
FDA-Approved Products and Clinical Data
The FDA has approved 4 cannabis-related products, including a cannabis-derived product (cannabidiol [Epidiolex®, GW Pharmaceuticals]) that contains a purified form of CBD. In June 2018, the FDA approved Epidiolex for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged ≥2 years (Table 2).16-19
The most well-studied clinical use of CBD is in the treatment of epilepsy. The antiseizure activity of CBD has been examined in animals with research dating back to the 1970s.20 Outside of the standard drug approval process, prospective clinical data associated with CBD is scarce, making claims of efficacy in different therapeutic areas difficult.
Khoury et al recently conducted a review of the clinical evidence supporting the use of CBD in psychiatric symptoms. Out of the 609 articles reviewed, the authors identified 6 case reports, 7 randomized clinical trials, and 21 registered clinical trials. Altogether, these studies included a total of only 201 subjects. The review concluded that the evidence is insufficient to support the use of CBD in psychiatric conditions.21
The lack of prospective clinical evidence regarding CBD should not lead to the conclusion that CBD lacks therapeutic potential. In addition to the studies leading to the approval of Epidiolex, extensive preclinical examination of CBD products has demonstrated promising therapeutic targets and speculation. One promising outcome of preclinical investigations is the potential for CBD to inhibit cancer.22 Researchers hypothesized that “through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis.”22 Although the preclinical studies appear promising, clinical trials have yet to demonstrate efficacy of CBD in the treatment of cancer, and further research is required.23 Other preclinical studies suggest a therapeutic application in the treatment of addiction.24 Anxiety, insomnia, and analgesia are all conditions routinely associated with the medicinal use of cannabis, and these conditions have been examined thoroughly in preclinical studies.3-5, 8-9
In addition to the scarcity of clinical data, current preclinical and clinical studies have not identified a conclusive dosing range for CBD. Currently, dosing of CBD ranges from 10 mg/d to 800 mg/d in studies, with tolerability observed in doses as high as 1500 mg/d.25 However, the CBD used in many studies was not a CBD-only product but rather a THC:CBD formulation. THC is potent at lower dosing and even a THC:CBD ratio of 1:25 may mask the effects of CBD by producing THC side effects.26
Due to decades of prohibition, medical cannabis was not subject to the traditional drug discovery process. As a result of the regulatory prohibition and subsequent liberalization of cannabis laws in just a few years, consumer availability and acceptance has outpaced clinical research efforts.