Cannabidiol and Other Cannabinoids: From Toxicology and Pharmacology to the Development of a Regulatory Pathway

abstract

Cannabidiol (CBD) is a non-psychotropic constituent of Cannabis sativa that has grown in popularity during the last decade. CBD is the active component of EPIDIOLEX®, a U.S. Food and Drug Administration (FDA)-approved drug designed for the treatment of drug-resistant pediatric epileptic seizures associated with several rare syndromes. Furthermore, CBD has been proposed as a treatment for a number of other diseases for which clinical trials are now ongoing. Accumulating evidence indicates that the number of “CBD-containing” products, available mostly online, is growing exponentially. However, the U.S. FDA currently prohibits sales of CBD as a dietary supplement (DS) or ingredient in conventional food. Further, clear federal regulatory and quality oversight does not exist, which has led to an uncontrolled CBD market that, in turn, threatens to result in negative health effects experienced by a trusting public. Thus, there are open questions demanding answers in the very near future: For which medical purposes is CBD provably effective? Can it be used safely as a non-prescription product? At what level? Is a hemp extract that contains CBD a different ingredient than isolated CBD? Is CBD safe for everyone? What is a future path for hemp products with CBD as well as for other cannabinoids? Should CBD be allowed as a drug only, or is there a way for hemp extracts to be listed as a dietary supplement and food ingredient? This Special Issue, the first of its kind on CBD and other phytocannabinoids, is devoted to answering those and other questions by publishing articles in the fields of pharmacology, toxicology, and regulation.

Keywords:

• Cannabidiol
• cannabis
• CBD
• dietary supplement
• endocannabinoid system
• hemp
• phytocannabinoids
• quality control
• regulations
• safety

Cannabidiol (CBD) is a non-psychotropic constituent of Cannabis sativa that has grown in popularity during the last decade. CBD is the active component of EPIDIOLEX®, a U.S. Food and Drug Administration (FDA)-approved drug designed for the treatment of drug-resistant pediatric epileptic seizures associated with several rare syndromes. Furthermore, CBD has been proposed as a treatment for a number of other diseases for which clinical trials are now ongoing.

Accumulating evidence indicates that the number of “CBD-containing” products, available mostly online, is growing exponentially. However, the U.S. FDA currently prohibits sales of CBD as a dietary supplement (DS) or ingredient in conventional food. Further, clear federal regulatory and quality oversight does not exist, which has led to an uncontrolled CBD market that, in turn, threatens to result in negative health effects experienced by a trusting public.

Thus, there are open questions demanding answers in the very near future: For which medical purposes is CBD provably effective? Can it be used safely as a non-prescription product? At what level? Is a hemp extract that contains CBD a different ingredient than isolated CBD? Is CBD safe for everyone? What is a future path for hemp products with CBD as well as for other cannabinoids? Should CBD be allowed as a drug only, or is there a way for hemp extracts to be listed as a dietary supplement and food ingredient?

This Special Issue, the first of its kind on CBD and other phytocannabinoids, is devoted to answering those and other questions by publishing articles in the fields of pharmacology, toxicology, and regulation.

Regulatory aspects

In the opening article for this Special Issue, Walker and colleagues provide their opinion on the perspectives on science, safety, and potential regulatory approaches for CBD in the United States (Walker et al. 2020). The authors note that the observed rapid expansion of marketed consumer CBD products, paralleled by the wide-ranging disease treatment claims, and the prevalence of substandard or even adulterated products, pose a serious public health and regulatory dilemma. Although the federal controlled substance status of hemp-derived CBD was relaxed as per the Agricultural Improvement Act of 2018 (a.k.a., “2018 Farm Bill”), the question of its regulatory status in DS was brought into sharp focus.

The authors advocate for the development of a nationwide stewardship program for CBD products and manufacturers. The goals of this program will be the identification of competent manufacturers and aiding with bringing their quality products to the market; ensuring there is a robust safety surveillance system; collaborative efforts with U.S. FDA in implementation of a regulatory reporting framework that shares the findings related to the program experience. This approach would consider establishing collaboration with trade organizations, manufacturers, academia, and nonprofit standards organizations (Walker et al. 2020).

Besides the U.S., cannabis extracts are becoming a focus of regulators and courts in Europe as its composition spans food, drug, and medicine laws. Of these extracts, CBD is the primary cannabinoid marketed as a health food in the European Union (EU). Its recent classification as a novel ingredient places a legal obligation on businesses to obtain prior authorization before its lawful sale. In these regards, the article by Tallon provides a review of the current and future challenges facing the food industry in the sale of CBD in the EU and the United Kingdom (Tallon 2020).

In June of 2018, as the U.S. FDA approved the New Drug Application (NDA) for EPIDIOLEX® – a purified CBD product – it seemingly precluded classification of CBD as a legal DS according to the current regulations. However, in their commentary, Marinotti and Sarill provide a perspective on differentiating the CBD-containing botanical hemp extracts that are marketed as dietary supplements from the FDA-approved pharmaceutical formulations of CBD (Marinotti and Sarill 2020). The authors argue that hemp-derived CBD supplements can contain a complex phytochemical matrix from the hemp plant, thus distinguishing the composition of these products from isolated CBD preparations. Cogan, though, in his counter opinion article provides another vision on this situation (Cogan 2020a). The latter article frames several arguments commonly used to distinguish whole plant hemp and broad spectrum cannabis products from purified cannabinoids as inherently flawed. For instance, the establishment of herbal extracts as dietary supplements – a provision of DSHEA hoped to be accessed by many in the cannabis industry – is challenged as a false dichotomy of herbs and drugs. Throughout, the paper, Cogan raises the question of whether considerations of composition and assessments of minimal preliminary data can stand as meaningful surrogates for the clinical effects of cannabis products when it comes to ensuring consumer safety and empowering consumer choice (Cogan 2020a).

Labeling and safety considerations

Safety of CBD and other cannabinoids remains a hotly debated topic. Data derived from clinical trials as well as experimental data (Devinsky et al. 2018; Ewing et al. 2019a) demonstrate that at high doses, CBD and CBD-rich cannabis extract pose significant risk for hepatotoxicity. Furthermore, accumulating evidence indicates CBD has a significant drug interaction potential that can further exacerbate hepatotoxicity (Ewing et al. 2019b; Anciones and Gil-Nagel 2020).

A study by Skinner and colleagues published in this Special Issue demonstrates that at high doses, CBD-rich cannabis extract can be detrimental to the gut as well (Skinner et al. 2020). Using a mouse model, the authors demonstrated a dose-dependent increase in certain bacterial species in fecal samples that was paralleled by decreases in the relative abundance of other gut bacterial species. Coincident with the observed changes in gut ecology were multiple pro-inflammatory responses, including increased expression of cytokines and chemokines as well as decreased expression of Muc2 – a gene intimately associated with gut integrity. These results raise concerns about a potential adverse impact on gut integrity with long-term usage of high doses of CBD (Skinner et al. 2020).

The study published in this Special Issue in which Lopez and colleagues investigated the safety of 15 mg/day of hemp-derived CBD ingested for the duration of 6 weeks in a randomized, placebo-controlled, double-blind clinical trial is of particular interest in these regards (Lopez et al. 2020). The dose used in this study was substantially lower than those used in clinical trials and the above-mentioned in vivo studies, and may be more reflective of the doses that would be used in DS. Importantly, the authors reported that all investigated values for hepato-renal function, as well cardiovascular health, fasting blood lipids, and whole blood cell counts remained within normal clinical limits with no between-group differences over time (Lopez et al. 2020).

Another important and the first of its kind contribution authored by Schmitz and colleagues performed a post marketing safety evaluation of Plus CBD^TM products (Schmitz et al. 2020). This assessment was conducted for the duration of 2 years and included a series of ingestible and topical products. The authors performed their analysis based on the adverse event reports from a total of approximately five million sold product units (Schmitz et al. 2020).

Product safety, however, starts from responsible manufacturing and labeling. In their study, Gurley and colleagues investigated the CBD, Δ⁹-tetrahydrocannabinol (THC), and synthetic cannabinoid content of 25 commercially available hemp oil products, obtained throughout the state of Mississippi (Gurley et al. 2020). The authors report that marked variability was observed between the actual CBD content and claimed quantities, as out of 25 products, only three were within ±20% of their label claim. Furthermore, THC content for three products exceeded the 0.3% legal limit and four products were adulterated with synthetic cannabinoids. The results of this study clearly demonstrated that most product label claims did not accurately reflect actual CBD content, and thus were considered fraudulent. The authors express their concerns in regards to potential legal and adverse health effects associated with products that exceeded legal THC levels and/or were adulterated with synthetic cannabinoids. Gurley and colleagues advocate for further development of current good manufacturing practices (cGMP) for CBD-containing products and their stringent enforcement (Gurley et al. 2020).

Efficacy

CBD and hemp extracts are touted for a wide range of health effects, most of which remain to be proven. In the article that opens this section, Cogan calls into question the wisdom of promoting therapeutic speculation to a poorly regulated and rapidly growing marketplace. He points to an endocannabinoid system defined by a diffuse and ever expanding matrix of molecules and asks if the so far vaguely characterized dysfunction of so complex a system can honestly be described as a simple cannabinoid “deficiency” (Cogan 2020b). The article further queries to what degree presumptive hypotheses and artifacts of pharmacological nomenclature might misinform or overestimate expectations of the therapeutic benefit from phytocannabinoid supplementation of this same system.

Clearly, there is an urgent need for experimental studies and clinical trials that would further investigate the therapeutic potential of CBD and other phytocannabinoids. Two studies published in this Special Issue provide some insight into the areas of prospective applications for CBD and CBD-rich cannabis extracts.

In the first article, Lopez and colleagues (2020), investigated the effects of a commercially available CBD-containing hemp oil extract on stress resilience, perceived recovery, mood, affect, and body composition in overweight, but otherwise healthy subjects (Lopez et al. 2020). The authors observed a significant improvement in the HDL cholesterol levels associated with hemp oil ingestion, as well some tendency to support psychometric measures of sleep, stress response, and perceived life pleasure.

In another study, Skinner et al. reported that in spite of negative effects on the gut health associated with high doses of CBD-rich cannabis extract (2020), the observed increase in the relative abundance of A. muciniphila can be considered as beneficial. A. muciniphila is a bacterial species that belongs to Bacteroides and is currently considered as probiotic as it is associated with lean phenotypes both in animals and in human studies (Henning et al. 2018; Gurley et al. 2019). The authors argue that the lower doses of CBD-rich cannabis extract may exert these beneficial effects on the gut microbiome without negatively affecting the gut integrity (Skinner et al. 2020).

In the final article in this Special Issue, Karimian Azari and colleagues provide a thorough literature review on the potentially beneficial effects of naturally occurring cannabinoids on the cardiovascular system (Karimian Azari et al. 2020). They discuss the role non-psychoactive endocannabinoids, terpenes, and the endocannabinoid-like molecule palmitoylethanolamide play in modulation of cardiovascular health. They further provide interesting perspectives on utilization of CBD and several minor cannabinoids, including investigation of activation of the endocannabinoid system as a cardioprotective compensatory mechanism (Karimian Azari et al. 2020).

Acknowledgements

We would like to take this opportunity to thank all the authors who contributed with their manuscripts for this Special Issue. We would also like to take this opportunity to thank all reviewers who kindly agreed to provide their valuable feedbacks on the submitted manuscripts. Last, but not list, we would like to thank Melody Harris, Sarah (Holstein) Williams, and Anjana Bhargavan from the Journal of Dietary Supplements Editorial Office and Taylor & Francis for all their efforts on this Special Issue.

Declaration of interest

The authors report no conflict of interest.

Additional information

Notes on contributors

Igor Koturbash

Igor Koturbash is an Associate Professor at the Department of Environmental and Occupational Health and Co-Director of the Center for Dietary Supplements Research at the University of Arkansas for Medical Sciences (UAMS) Fay W. Boozman College of Public Health. Being both MD and PhD, Dr. Koturbash has long been interested in diet and dietary supplements and their impact on human health. Therefore, the major focus of his research is safety, efficacy, and mechanisms of action of dietary supplements and understanding how diet and dietary supplements can modulate tissue response to cancer therapy. Igor is heavily involved in a number of safety and efficacy studies on various dietary supplements and herbs, including methionine supplementation, green tea extract, and cannabidiol (CBD), to name a few. Igor has published 90+ peer-reviewed articles and book chapters, and his research has received uninterrupted extramural funding from various sources since the beginning of his independent career.

Douglas MacKay

Douglas “Duffy” MacKay, N.D. is a Senior Vice President for Scientific and Regulatory Affairs at CV Sciences, Inc., manufacturers of a hemp extract with cannabidiol (CBD). Dr. MacKay is responsible for scientific and regulatory affairs functions that drive product quality, safety and innovation. Dr. MacKay comes to CV Science after a ten-year career with the Council for Responsible Nutrition (CRN) where he served as the SVP, scientific and regulatory affairs. Dr. MacKay oversaw the scientific and regulatory affairs department, ensuring that the association’s scientific, policy and legislative positions were based on credible scientific rationale. He also serves, on the CRN Board of Directors; Journal of Dietary Supplements, Associate Editor; American Botanical Council (ABC), Advisory Board and FDLI Cannabis-Derived Products Committee, as well as the editorial boards of Integrative Medicine a Clinician’s Journal, and Natural Medicine Journal.