Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders, Francisco Navarrete et al., 2021

Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders

Francisco Navarrete, María Salud García-Gutiérrez, Ani Gasparyan, Amaya Austrich-Olivares and Jorge Manzanares

Frontiers in Pharmacology, 2021, 12, Article 696010, 1-24.

Doi : 10.3389/fphar.2021.626010


Drug treatments available for the management of substance use disorders (SUD) present multiple limitations in efficacy, lack of approved treatments or alarming relapse rates. These facts hamper the clinical outcome and the quality of life of the patients supporting the importance to develop new pharmacological agents. Lately, several reports suggest that cannabidiol (CBD) presents beneficial effects relevant for the management of neurological disorders such as epilepsy, multiple sclerosis, Parkinson’s, or Alzheimer’s diseases. Furthermore, there is a large body of evidence pointing out that CBD improves cognition, neurogenesis and presents anxiolytic, antidepressant, antipsychotic, and neuroprotective effects suggesting potential usefulness for the treatment of neuropsychiatric diseases and SUD. Here we review preclinical and clinical reports regarding the effects of CBD on the regulation of the reinforcing, motivational and withdrawal-related effects of different drugs of abuse such as alcohol, opioids (morphine, heroin), cannabinoids, nicotine, and psychostimulants (cocaine, amphetamine). Furthermore, a special section of the review is focused on the neurobiological mechanisms that might be underlying the ‘anti-addictive’ action of CBD through the regulation of dopaminergic, opioidergic, serotonergic, and endocannabinoid systems as well as hippocampal neurogenesis. The multimodal pharmacological profile described for CBD and the specific regulation of addictive behavior-related targets explains, at least in part, its therapeutic effects on the regulation of the reinforcing and
motivational properties of different drugs of abuse. Moreover, the remarkable safety profile of CBD, its lack of reinforcing properties and the existence of approved medications containing this compound (Sativex®, Epidiolex®) increased the number of studies suggesting the potential of CBD as a therapeutic intervention for SUD. The rising number of publications with substantial results on the valuable therapeutic innovation of CBD for treating SUD, the undeniable need of new therapeutic agents to improve the clinical outcome of patients with SUD, and the upcoming clinical trials involving CBD
endorse the relevance of this review.

Keywords : cannabidiol, substance use disorder, alcohol, cocaine, cannabis, psychostimulant, neurobiology



Substance Use Disorders (SUD) are chronic and relapsing clinical conditions meeting the diagnostic criteria for drug dependence defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (APA, 2013) and the World Health Organization’s International Classification of Diseases (ICD- 11) (World Health Organization, 2018). SUD are one of the most important health problems globally. In 2017, it was estimated that over 30 million individuals present an SUD leading to more than 31 thousand years lived with disability (YLDs) with a worrying increase (16.7%) over the previous decade (GBD 2017 Disease and Injury Incidence and Prevalence Collaborators, 2018). Furthermore, substance use was indirectly and directly responsible for 11.8 million deaths which implies one in five deaths worldwide (GBD 2017 Disease and Injury Incidence and Prevalence Collaborators, 2018).

Despite the range of the psychosocial and pharmacological therapeutic approaches for substance use treatment, relapse prevalence into drug consumption is estimated between 40 and 75% (Sinha, 2011; Pasareanu et al., 2016; Andersson et al., 2019). This high rate of recurrence is largely due to the
ineffectiveness of the available drugs or the lack of specific treatments (e.g., cannabis, cocaine, or amphetamine-type use disorders). Thus, there is a growing need to significantly improve our knowledge about the underlying mechanisms involved in the development of drug dependence to finally design new pharmacological tools with higher efficacy and safety. In this sense, the manipulation of the endocannabinoid system (ECS) by administering cannabinoid compounds has raised much interest due to its close functional involvement in the regulation of emotion, cognition, and reward (Solinas et al., 2008; Marco et al., 2011; Campolongo and Trezza, 2012; Marco and Laviola, 2012; Manzanares et al., 2018; Navarrete et al., 2020).

Cannabis sativa plant contains numerous chemical entities including cannabinoids, terpenes, and phenolic compounds (Andre et al., 2016). To date, over 120 cannabinoids have been isolated from the plant (Morales et al., 2017). From these, delta-9- tetrahydrocannabinol (THC) is the main psychotomimetic or hallucinogenic component and the first cannabinoid to be identified and studied. First described and synthesized by Roger Adams in 1942 (Adams, 1942), and then isolated for the first time by Gaoni and Mechoulam in 1964 (Gaoni and Mechoulam, 1964), THC mediates the rewarding properties of cannabis (Zhang et al., 2004). Along with THC, cannabidiol (CBD) is the other most abundant phytocannabinoid in the Cannabis sativa plant. It was first synthesized by Roger Adams (Adams, 1942) and isolated by Mechoulam and Shvo in 1963 (Mechoulam et al., 1963), from which a growing interest in its pharmacological actions began to emerge. The results from basic and clinical studies suggested that CBD may present beneficial effects for the management of neurological disorders such as epilepsy (Carlini and Cunha, 1981; Devinsky et al., 2014; Devinsky et al., 2016), multiple sclerosis (Kozela et al., 2011; Giacoppo et al., 2015; Jones and Vlachou, 2020), Parkinson’s (Zuardi et al., 2009; Chagas et al., 2014) or Alzheimer’s diseases (Martín-Moreno et al., 2011; Cheng et al., 2014). Moreover, there is a growing body of evidence suggesting that CBD improves cognition (Osborne et al., 2016) and neurogenesis (Liput et al., 2013; Schiavon et al., 2016), and presents antipsychotic (Zuardi et al., 1991; Moreira and Guimarães, 2005; Long et al., 2006; Leweke et al., 2012; Leweke et al., 2016; Peres et al., 2016), anxiolytic (Guimarães et al., 1990; Moreira et al., 2006; Resstel et al., 2006; Blessing et al., 2015) and antidepressant-like effects (Zanelati et al., 2010; Linge et al., 2016; Sartim et al., 2016). All these potential therapeutic actions of CBD are due to its multiple pharmacological mechanisms. CBD was proposed to directly or indirectly modulate the function of more than 65 targets in the central nervous system (CNS) (Ibeas Bih et al., 2015), including cannabinoid receptors (CB1, CB2), GPR55 receptor, vanilloid receptor TRPV1, serotonin 5HT1a receptor (Bisogno et al., 2001; Russo et al., 2005; Ryberg et al., 2007; Thomas et al., 2007; Campos et al., 2012), the anandamide (AEA) hydrolyzing enzyme (fatty acid amide hydrolase, FAAH) or the adenosine transporter (Carrier et al., 2006; Massi et al., 2008). However, additional studies are needed to precisely determine the target engagement profile of CBD.

Importantly, CBD lacks addictive potential in contrast to THC. Several studies in animals and humans demonstrated the absence of rewarding properties (Parker et al., 2004; Katsidoni et al., 2013; Babalonis et al., 2017; Schoedel et al., 2018). Indeed, recent studies carried out in mice in our laboratory further demonstrate that CBD is not an addictive substance. A range of CBD doses were evaluated in different animal models of addiction commonly used to assess the reinforcing and motivational properties of drugs (conditioned place preference (CPP) and oral self-administration (SA)). Also, withdrawalrelated signs were analyzed after the abrupt cessation of CBD chronic administration. Interestingly, CBD did not induce CPP, oral SA or withdrawal-related signs, findings that suggested the lack of rewarding effects of CBD (Viudez-Martínez et al., 2019). Moreover, CBD presents an excellent safety profile supported by both animal and clinical studies (Bergamaschi et al., 2011; Iffland and Grotenhermen, 2017; Taylor et al., 2018). Proof of this is the recent marketing of the drug Epidiolex®, a 99% pure oral CBD extract for the treatment of refractory childhood epilepsies (Lennox-Gastaut and Dravet syndrome) (Sekar and Pack,
2019; Raucci et al., 2020). Likewise, nabiximols is another marketed formulation containing CBD and THC (25 and 27 mg/ml, respectively) under the trade name Sativex®. Nabiximols is an oromucosal spray widely employed for the treatment of muscle spasticity in multiple sclerosis patients (Patti et al., 2016; Giacoppo et al., 2017).

Therefore, the versatile pharmacological profile and safety of CBD support its therapeutic potential in the management of SUD. This review focuses on collecting all the available evidence about the effects of CBD on the different aspects that accompany drug dependence (reinforcement, motivation, contextual
conditioning, relapse, withdrawal syndrome or motor sensitization). Also, it covers all the mechanisms proposed to mediate the CBD actions on drug addiction.