The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets
Rosa Maria Vitale, Fabio Arturo Iannotti and Pietro Amodeo
International journal of Molecular Sciences, 2021, 22, 4876, 1-20.
Doi : 10.3390/ijms22094876
Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.
Keywords : cannabidiol; pharmacology; neuropsychiatric disorders; receptors; pharmacological targets
Cannabidiol (CBD, Figure 1), along with D9-tetrahydrocannabinol (D9-THC), is the most abundant bioactive compound of Cannabis sativa. Differently from D9-THC, it is devoid of any psychotropic effects . Interestingly, D9-THC and CBD are often considered the yin and the yang of cannabis extract for their antithetic effects: D9-THC binds with high affinity and activates cannabinoids receptors, responsible for the rewarding effects of cannabis, while CBD has a low affinity for the orthosteric sites of those receptors and acts as negative allosteric modulator (NAM) at Cannabinoid receptor 1 (CB1R) in
the nanomolar range . The NAM effect of CBD at CB1R was confirmed in a recent study by Tham et al.  while at CB2R it behaves as partial agonist. Moreover, CBD counteracts the anxiogenic effects of D9-THC and, due to its effects in inhibiting drug relapse, is currently under investigation for the treatment of addiction disorders . CBD, whose structure was elucidated by Mechoulam and Shvo  in 1963, has been recently approved by the US Food and Drug Administration (FDA) and the European Medicines
Agency (EMA) as an antiepileptic drug (Epidiolex) for the treatment of patients affected by refractory epilepsy such as Dravet  and Lennox–Gastaut syndromes . Here, we discuss the therapeutic potential of CBD in neurological and neuropsychiatric disorders with particular emphasis on the involved molecular targets and mechanisms. The review is organized in two main sections: the first one reports an overview of the pharmacological effects of CBD in neurological and neuropsychiatric disorders, the second one describes the molecular targets and the molecular mechanisms involved in these effects. Structural details from experimental structures of the ligand-binding sites are also discussed, along with mutagenesis data.