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The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets

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The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets International Journal of Molecular Sciences Review The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets Rosa Maria Vitale 1,* , Fabio Arturo Iannotti 1,2 and Pietro Amodeo 1 1 Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy; [email protected] (F.A.I.); [email protected] (P.A.) 2 Endocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy * Correspondence: [email protected]; Tel.: +39-0818-675-316 Abstract: 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. Citation: Vitale, R.M.; Iannotti, F.A.; Amodeo, P. The (Poly)Pharmacology Keywords: cannabidiol; pharmacology; neuropsychiatric disorders; receptors; pharmacological targets of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets. Int. J. Mol. Sci. 2021, 22, 4876. 1. Cannabidiol https://doi.org/10.3390/ijms22094876 Cannabidiol (CBD, Figure1), along with D9-tetrahydrocannabinol (D9-THC), is the most abundant bioactive compound of Cannabis sativa. Differently from D9-THC, it is Academic Editor: Aron Weller devoid of any psychotropic effects [1]. Interestingly, D9-THC and CBD are often considered the yin and the yang of cannabis extract for their antithetic effects: D9-THC binds with Received: 15 April 2021 high affinity and activates cannabinoids receptors, responsible for the rewarding effects Accepted: 3 May 2021 Published: 5 May 2021 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 Publisher’s Note: MDPI stays neutral the nanomolar range [2]. The NAM effect of CBD at CB1R was confirmed in a recent with regard to jurisdictional claims in study by Tham et al. [3] while at CB2R it behaves as partial agonist. Moreover, CBD 9 published maps and institutional affil- counteracts the anxiogenic effects of D -THC and, due to its effects in inhibiting drug iations. relapse, is currently under investigation for the treatment of addiction disorders [4]. CBD, whose structure was elucidated by Mechoulam and Shvo [5] 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 [6] and Lennox–Gastaut syndromes [7]. Here, we Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. discuss the therapeutic potential of CBD in neurological and neuropsychiatric disorders This article is an open access article with particular emphasis on the involved molecular targets and mechanisms. The review distributed under the terms and is organized in two main sections: the first one reports an overview of the pharmacological conditions of the Creative Commons effects of CBD in neurological and neuropsychiatric disorders, the second one describes Attribution (CC BY) license (https:// the molecular targets and the molecular mechanisms involved in these effects. Structural creativecommons.org/licenses/by/ details from experimental structures of the ligand-binding sites are also discussed, along 4.0/). with mutagenesis data. Int. J. Mol. Sci. 2021, 22, 4876. https://doi.org/10.3390/ijms22094876 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 24 targets and the molecular mechanisms involved in these effects. Structural details from Int. J. Mol. Sci. 2021, 22, 4876 experimental structures of the ligand-binding sites are also discussed, along with muta-2 of 20 genesis data. (a) (b) FigureFigure 1. 2D 1. 2D(a) and (a) and 3D 3D(b) (representationsb) representations of ofcannabidiol cannabidiol (C (CBD).BD). Hydroxyl Hydroxyl group group (2D (2D view)/oxy- view)/oxygen genatoms, atoms, carboncarbon atomsatoms and hydrogen atoms atoms (3 (3DD view) view) are are colored colored red, red, dark dark slate slate gray gray and and white, white,respectively. respectively. Only Only polar polar and and stereo stereo hydrogen hydrogen atoms atoms (the (the latter latter colored colored in gray) in gray) are shownare shown in (a ). in (a). 2. Neurological and Neuropsychiatric Disorders Potentially Affected by 2. NeurologicalCBD Treatment and Neuropsychiatric Disorders Potentially Affected by CBD Treatment2.1. Epilepsy and Cannabidiol 2.1. EpilepsyEpilepsy and Cannabidiol is a very frequent group of neurological disorders affecting around 50 million people worldwide. It is caused by excessive and abnormal brain activity, characterized Epilepsy is a very frequent group of neurological disorders affecting around 50 mil- by recurrent seizures and neuropsychiatric comorbidities, which negatively affect the lion people worldwide. It is caused by excessive and abnormal brain activity, character- quality of life of patients. Despite the multiple antiepileptic drugs (AEDs) available, about ized by recurrent seizures and neuropsychiatric comorbidities, which negatively affect the one-third of adults and approximately 20–25% of children have forms of epilepsy that quality of life of patients. Despite the multiple antiepileptic drugs (AEDs) available, about do not respond to drug therapy [8] and frequently these patients receive higher doses of one-third of adults and approximately 20–25% of children have forms of epilepsy that do multi-AED regimens that are not only ineffective but also cause unpleasant side effects. not respond to drug therapy [8] and frequently these patients receive higher doses of For this reason, there is still an urgent need to find treatments against drug-resistant multi-AED regimens that are not only ineffective but also cause unpleasant side effects. epilepsy (DRE) [9,10]. In this view, CBD has received great scientific interest due to its For this reason, there is still an urgent need to find treatments against drug-resistant epi- anticonvulsant proprieties, as revealed in experimental animal models of epilepsy [11]. lepsy (DRE) [9,10]. In this view, CBD has received great scientific interest due to its anti- Notably, CBD (Epidiolex), recently reviewed by Abu-Sawwa and Park [12], has been the convulsantfirst cannabis-derived proprieties, as medicationrevealed in experime approvedntal in animal 2018 by models the FDA of epilepsy for patients [11].≥ Nota-2 years bly,of CBD age diagnosed(Epidiolex), with recently rare formsreviewed of AEDs-refractory by Abu-Sawwa and epilepsy Park such[12], ashas Dravet been the syndrome first cannabis-derived(DS) and Lennox-Gastaut medication syndromeapproved in (LGS). 2018 Theby the molecular FDA for targets patients possibly ≥2 years involved of age in diagnosedmediating with the rare therapeutical forms of effectsAEDs-refractor of CBD iny epilepsy epilepsy include such asγ -aminobutyricDravet syndrome acid (GABA)(DS) and Lennox-Gastaut syndrome (LGS). The molecular targets possibly involved in medi- A receptors (GABAARs, Section 3.1.1), glycine receptors (GlyRs, Section 3.1.2), transient atingreceptor the therapeutical potential cation effects channel of CBD subfamily in epilepsy V memberinclude γ 1-aminobutyric (TRPV1, Section acid 3.2.1 (GABA)), transient A receptorsreceptor (GABA potentialARs, ankyrinSection subtype3.1.1), glycine 1 protein receptors (TRPA1) (GlyRs, and possibly Section TRPV23.1.2), transient (Section re-3.2.2), ceptorand potential GPR55 (Section cation 3.3.4channel). subfamily V member 1 (TRPV1, Section 3.2.1), transient receptor potential ankyrin subtype 1 protein (TRPA1) and possibly TRPV2 (Section 3.2.2), and2.2. GPR55 Alzheimer’s (Section Disease 3.3.4). and Cannabidiol Alzheimer’s disease (AD) is a neurodegenerative disorder associated with progressive 2.2.memory Alzheimer’s and Disease cognitive and impairment,Cannabidiol which severely compromises the ability to carry out everydayAlzheimer’s tasks. disease It represents (AD) is the a neurodegen most commonerative cause disorder of dementia, associated accounting with progres- for 60–70% siveof memory cases (World and cognitive Health Organization, impairment, which 2020). severely The two compromises pathological the hallmarks ability to of carry AD are outthe everyday deposition tasks. of Itβ represents-amyloid ( βtheA) most peptide, common leading cause to senileof dementia, plaques, accounting and the hyperphos- for 60– 70%phorylation of cases (World of tau Health protein, Organization, forming neurofibrillary 2020). The
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