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Mechoulam, R., Parker, L. A. & Gallily, R. Cannabidiol: an overview of some pharmacological aspects. J. Clin. Pharmacol. 42(S1), 11S–19S (2002).

C.M. conceived the experiments, C.M. conducted the experiments, C.M., E.F., M.P. and M.L. analysed the results. All authors reviewed the manuscript.

Acknowledgements

In 2018, the FDA approved the only therapeutic application of cannabidiol, a pure, plant-based, pharmaceutical grade extract known as Epidiolex, for the treatment of two rare and severe forms of epilepsy, Lennox-Gastaut and Dravet syndromes. In clinical trials and research studies, CBD has been administered orally as either a capsule or dissolved in an oil solution. Unfortunately, its oral bioavailability has been estimated to be 6%, due to significant first-pass metabolism 12 , which has resulted in doses ranging from 100 up to 800 mg/day 13 . According to the manufacturer, GW Pharmaceuticals, Epidiolex costs a patient, without insurance, $32,500 per year hence, despite the high tolerance level of CBD 14 , routes with higher bioavailability, which in turn result in lower doses, would be particularly desirable. Inhalation of phytocannabinoids have been proved to be one of the most efficient administration route in terms of bioavailability with values reaching around 30% 15 . Besides smoking cigarettes, new devices have been developed to vaporize phytocannabidiols that use electric power to heat the product to the point of vaporization. Electronic cigarettes (EC) are battery-powered portable vaporizer devices and since their first introduction in 2003 as an alternative route to traditional tobacco for nicotine delivery system, they have steadily gained popularity among adults and adolescents becoming in the latter, a more common tobacco product than conventional cigarettes 16,17,18 . In EC, nicotine is dissolved in a solution made of variable ratios of two chemical compounds, namely propylene glycol (PG) and vegetable glycerine (VG), and added flavours to form a liquid, known as e-liquid, which is then vaporized by a coil. Several studies have shown that PG and VG can undergo thermal degradation during vaping to form toxic and potentially toxic compounds among which formaldehyde, acetaldehyde and acrolein 19 . Their concentration is strictly related to the operative conditions of the devices and increases with increasing temperatures due to high battery output voltages applied to EC 20 . Following the recent legalization of cannabis in some U.S. states, there has been a blooming of e-liquids containing cannabinoids on the market worldwide as a new drug delivery system. In particular, several CBD products have become available with a wide range of concentrations (from 10 up to 100 mg per mL of solution) and medicinal claims. The continuous misleading labels of these products prompted the FDA in 2015 and 2016 to issue warning letters to companies marketing an unapproved drug in their products for therapeutic benefits 21 . Furthermore, two separated studies have highlighted the discrepancy between the declared labelled concentrations of cannabinoids and the real contents. Indeed, Pearce et al. analysed two commercial marijuana e-liquids claiming to contain 3.3 mg/mL CBD and found that the real contents were around twice as much 22 . In 2017, FDA carried out tests on the chemical content of CBD in commercially available products confirming this label inaccuracy 23 . Another aspect that needs to be addressed is the storage stability of e-liquids containing CBD. To date no studies have been published on the influence of storage conditions on the quality of these products. These lacking data are extremely important considering the chemical stability of CBD that undergoes oxidation in presence of oxygen to form mono- and dimeric hydroquinones and degradation when exposed to light 24 . Temperature could be another important factor in terms of quality of the final product to be monitored during shipping and storage. The aim of these studies was to investigate the feasibility of EC as a potential alternative CBD delivery system by gaining information on the actual state of the accuracy in labelling e-liquids containing CBD and by providing explorative data on their best storage conditions.

The effect of light on the thirteen samples was also investigated by storing the solutions for 30 days at RT (same samples used for the thermal stability studies) placing alongside two identical samples of 1 mL each, one wrapped in aluminium foil (dark control, Table 2 entry CF at RT), under a natural day light exposure. Results (Table 3, percent difference rt + photo) showed a net detrimental effect of light on the chemical stability of CBD with an average decrease in the CBD concentration of 13% against samples conserved in the dark which showed an average decrease of 4%. Statistical analyses indicated that samples D, E, H, M, O did not undergo to a significant CBD decrease between treatments while all the other were significantly affected in their final CBD concentration by light exposure.

Grotenhermen, F. Cannabis and Cannabinoids-Pharmacology, Toxicology, and Therapeutic Potential (eds Grotenhermen, F. & Russo, E.) 55–65 (Haworth Press, 2002).