Cannabidiol: State of the art and new challenges for therapeutic applications, Simona Pisanti et al., 2017 ,

Cannabidiol: State of the art and new challenges for therapeutic applications

Simona Pisanti, Anna Maria Malfitano, Elena Ciaglia, Anna Lamberti, Roberta Ranieri, Gaia Cuomo,
Mario Abate, Giorgio Faggiana, Maria Chiara Proto, Donatella Fiore, Chiara Laezza, Maurizio Bifulco

Pharmacology & Therapeutics, 2017, 175, 133-150

DOI : 10.1016/j.pharmthera.2017.02.041

 a b s t r a c t

Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ9-THC and cannabidiol (CBD) are themost abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ9-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in neurological diseases and cancer.
© 2017 Published by Elsevier Inc

Keywords : Cannabis, Cannabidiol, Endocannabinoid system, Neurological diseases, Cancer


1. Introduction
1.1. Phytocannabinoids: focus on CBD
Cannabis sativa contains hundreds of chemical entities produced by secondary metabolism including, beyond cannabinoids, terpenes and phenolic compounds, each one with potential interesting biological properties (Andre, Hausman, & Guerriero, 2016). Known cannabinoids are more than 90, even if some derive from breakdown reactions. Currently, the scientific community indicates with the term ‘cannabinoid’ these terpenophenols derived from Cannabis sativa but also synthetic compounds able to directly or indirectly act on cannabinoid receptors (Appendino, Chianese, & Taglialatela-Scafati, 2011). Delta-9- tetrahydrocannabinol (Δ9-THC) is the main component of Cannabis sativa and the first cannabinoid to be discovered and studied, well known for its psychoactive effects (Russo, 2011). Among the other major phytocannabinoids isolated from the plant there are: CBD (Mechoulam & Shvo, 1963), cannabichromene (CBC) (Gaoni & Mechoulam, 1966), cannabigerol (CBG) (Gaoni & Mechoulam, 1964), cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV) (Gill, Paton, & Pertwee, 1970; Vollner, Bieniek, & Korte, 1969) (Table 1). Although these compounds have similar chemical structures, they can elicit different pharmacological actions. Mainly, their pharmacological properties rely on the interaction with components of the endocannabinoid systemmachinery like cannabinoid receptors and enzymes of endocannabinoid synthesis and degradation. Focusing on CBD, it is well known that this compound is the second major comonent of the plant, themost prevalent in the fibre-type hemp, it is not associated
with psychoactivity and does not affect motor function, memory or body temperature on its own. It displays with respect to Δ9-THC lower CB1 and CB2 receptor affinity (Bisogno et al., 2001; Pertwee, 1999; Showalter, Compton, Martin, & Abood, 1996; Thomas, Gilliam, Burch, Roche, & Seltzman, 1998) and it was found to be an inverse agonist at the human CB2 receptor, property that may contribute to its antiinflammatory effects (Thomas et al., 2007). Beyond numerous per se pharmacological effects, CBD acts as an entourage molecule, reducing the collateral effects of Δ9-THC, thus ameliorating its safety profile.