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.
CBD oil, a common formulation, is a concentrated extract dissolved in an edible oil.27 The use of solvents to extract the CBD varies among producers and can affect color, taste, and viscosity. Oil is favored among consumers due to the ease of ingestion, ability to receive high concentrated dosing, and avoidance of stigma that may be associated with smoking or vaping.27 However, CBD oil is poorly absorbed in the gastrointestinal tract, and oral bioavailability of CBD oil has been estimated at 6%.28 Aerosolized CBD has greater bioavailability than oral administration and rapid peak plasma concentrations.28
CBD is primarily metabolized through the liver; the 2 main cytochrome pathways involved are CYP3A4 and CYP2D6.29 More drugs are metabolized via CYP3A than any other P450 enzyme.30 The effects of CBD dose and absorption on drug-drug interaction requires further research.
CBD consumption is not associated with risk of intoxication.31 Due to scarce clinical evidence, the available data on proper dosage, drug-drug interactions, and side effects are limited. In a review of the available evidence, CBD does not appear to change appetite or alter physiologic parameters, psychomotor functioning, or gastrointestinal transit time.27 Studies suggest chronic dosing of CBD up to 1500 mg/d is well tolerated.24 CBD does appear to affect hepatic drug metabolism and p-glycoprotein transporters.24 Pure CBD does not appear to have any recreational or abuse potential. In a World Health Organization report, the available literature reviewed demonstrated CBD to be well tolerated with a favorable safety profile.32
The FDA encourages clinicians to warn patients about purchasing CBD products online. “Selling unapproved products with unsubstantiated therapeutic claims — such as claims that CBD products can treat serious diseases and conditions — can put patients and consumers at risk by leading them to put off important medical care. Additionally, there are many unanswered questions about the science, safety, effectiveness and quality of unapproved products containing CBD,” said Acting FDA Commissioner Ned Sharpless, MD.33
CBD Drug Development Pipeline
Despite the availability of CBD in retail settings, CBD drug development is still an essential step toward the adoption and understanding of cannabis-based medicine. The rigorous drug development process provides valuable insight into the pharmacologic effects of a drug through phase 1, 2, and 3 studies. Drug development also provides a means of accountability for manufacturers through regulatory and peer-reviewed methods of oversight. To that end, several pure CBD drugs are currently in development (Table 3).34-38
CBD demonstrates promise in preclinical research, and numerous pharmaceutical companies are pursuing cannabis-based drug development. Recent regulatory changes have led to the explosion of CBD availability in retail and online markets. The quality and consistency of these CBD products are highly variable, which can lead to efficacy and safety concerns for consumers. In an ideal scenario, CBD products would not be available to consumers until they have been approved by the FDA; however, the genie is out of the bottle and clinicians are seeing an increase in the volume of questions from their patients regarding the use of CBD.
While many issues remain unresolved, CBD appears to be well tolerated and safe. Clinicians must weigh the risks and potential benefits of CBD use in their patients. If clinicians choose to recommend CBD, they should ensure that their patients understand the importance of reputable product sourcing and the possibility of unreported THC content, which can cause positive drug testing among other potential unintended effects.
Cannabis appears to be an exciting new frontier in drug development. The recent shift in public opinion and subsequent legalizations in various states have led to a rapid explosion of use and public adoption, with clinical research lagging behind. The lack of clinical research should not prompt clinicians to be pessimistic but rather cautiously acknowledge that the conclusive evidence is still pending.
Michael Asbach, MPAS, PA-C, Psy-CAQ is a physician assistant at DENT Neurologic Institute in Amherst, New York.
- Franck T. Top cannabis analyst of Wall Street raises sales forecast, names top 2019 picks. CNBC. https://www.cnbc.com/2019/01/08/top-weed-analyst-on-wall-street-raises-sales-forecast-names-top-picks.html. Accessed September 7, 2019.
- Governing. State Marijuana Laws in 2019 Map. https://www.governing.com/gov-data/safety-justice/state-marijuana-laws-map-medical-recreational.html. Accessed October 30, 2019,
- Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol. 2012;2(6):241-254.
- Iffland K, Grotenhermen F. An update of safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis Cannabinoid Res. 2017;2(1):139-154.
- Aizpurua-Olaizola O, Soydaner U, Öztürk E, et al. Evolution of the cannabinoid and terrine content during the growth of Cannabis sativa plants from different chemotypes. J Nat Prod. 2016;79(2):324-331.
- Manzanares J, Julian MD, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol. 2006;4(3):239-257.
- Mead A. The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law. Epilepsy Behav. 2017;70:288-291.
- Iseger TA, Bossong MG. A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr Res. 2015;162(1-3):153-161.
- Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27(1):19-27.
- US Department of Agriculture. 2018 Farm Bill. Subtitle G—Hemp Production. https://www.ams.usda.gov/sites/default/files/media/2018FarmBill.pdf Accessed October 30, 2019.
- Drug Enforcement Agency. DEA announces steps necessary to improve access to marijuana research. https://www.dea.gov/press-releases/2019/08/26/dea-announces-steps-necessary-improve-access-marijuana-research. Accessed October 30, 2019.
- A Regulation of Cannabis and Cannabis-Derived Products: Questions and Answers. FDA. https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-questions-and-answers#statesallowing. Accessed August 31, 2019.
- Warning letters and test results for cannabidiol-related products. FDA. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products. Accessed August 31, 2019.
- De Meijer EPM, Bargatta M, Carboni A, et al. The inheritance of chemical phenotype in Cannabis sativa L. Genetics. 2003;163(1): 335-346.
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- Food & Drug Administration. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm Accessed August 31, 2019.
- Food and Drug Administration. Marinol package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018651s029lbl.pdf. Accessed October 31, 2019.
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- Do Val-da Silva RA, Peixoto-Santos JE, Kandratavicius L, et al. Protective effects of cannabidiol against seizures and neuronal death in a rat model of mesial temporal lobe epilepsy. Front Pharmacol. 2017;8:131.
- Khoury JM, Neves MCLD, Roque MAV, et al. Is there a role for cannabidiol in psychiatry? World J Biol Psychiatry. 2019;20(2):101-116.
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This article originally appeared on Clinical Advisor