CB2 Receptor Involvement in the Treatment of Substance Use Disorders, Francisco Navarrete et al., 2021

CB2 Receptor Involvement in the Treatment of Substance Use Disorders

Francisco Navarrete, María S. García-Gutiérrez, Ani Gasparyan, Daniela Navarro and Jorge Manzanares

Biomolecules, 2021, 11, 1556, 1-18.

Doi : 10.3390/biom11111556



The pharmacological modulation of the cannabinoid receptor 2 (CB2r) has emerged as a promising potential therapeutic option in addiction. The purpose of this review was to determine the functional involvement of CB2r in the effects produced by drugs of abuse at the central nervous system (CNS) level by assessing evidence from preclinical and clinical studies. In rodents, several reports suggest the functional involvement of CB2r in the effects produced by drugs of abuse such as alcohol, cocaine, or nicotine. In addition, the discovery of CB2r in brain areas that are part of the reward system supports the relevance of CB2r in the field of addiction. Interestingly, animal studies support that the CB2r regulates anxiety and depression behavioral traits. Due to its frequent comorbidity with neuropsychiatric disorders, these pharmacological actions may be of great interest in managing SUD. Preliminary clinical trials are focused on exploring the therapeutic potential of modulating CB2r in treating addictive disorders. These promising results support the development of new pharmacological tools regulating the CB2r that may help to increase the therapeutic success in the management of SUD.

Keywords : cannabinoid 2 receptor; substance use disorder; reward system; alcohol; cocaine; nicotine


1. Introduction

Substance use disorder (SUD) is a chronic and relapsing mental illness characterized by compulsive drug seeking and the repeated achievement of episodes of intoxication and withdrawal. It is a clinical entity diagnosed according to the criteria of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) [1]. Such measures enter into the following subgroups: (1) alterations in the control of substance use, (2) impairment of the social component, (3) use under risk conditions, and (4) development of tolerance. These may include the lack of control of substance use occurring often or more extended periods than initially planned. These alterations may also have an intense desire and a high degree of impulsivity, which translate into an almost exclusive dedication to the search, consumption, and recovery of the effects induced by the substance.

According to the latest report issued by the United Nations Office on Drugs and Crime (UNODC), approximately 275 million people worldwide consumed some drug of abuse at least once during 2019 [2]. Thirty-one million people who use drugs meet diagnostic criteria for SUD and are candidates for treatment. According to the World Health Organization (WHO) data, deaths directly related to SUD amounted to 167,750 in 2015, representing a 60% increase over the previous figure of 2000. Opioids produce the highest morbidity and mortality among the drugs consumed, accounting for 76% of the deaths mentioned above (mainly due to overdose). On the other hand, alcohol constitutes the most consumed legal drug, globally ranking seventh as a cause of death or loss of quality of life [3]. Likewise, cannabis is the illegal drug with the highest percentage of users, amounting to 192 million during 2016 [2].

One of the most significant difficulties accompanying the therapeutic approach to SUD is the low rate of people who, meeting diagnostic criteria, finally receive adequate treatment, currently estimated as seven in eight people [2]. A worrying fact is the lack of suitable drugs to reach complete dishabituation or significant reduction in consumption, minimizing the associated risks. Proof of this is the absence of approved treatments for withdrawal from cannabis, cocaine, or amphetamine derivatives. In these cases, symptomatic approaches may reduce characteristic components after cessation of use, such as anxiety or irritability. Even for drugs officially approved to treat alcohol, tobacco, or opiate dependence by the leading regulatory agencies Food and Drug Administration (FDA) in the United States, or the European Medicines Agency (EMA) in Europe, the percentage of patients recovering entirely or partially is significantly reduced. In this sense, it is essential to improve our knowledge of the neurobiological bases underlying the addictive process for all these reasons. In this regard, it is crucial to identify the mechanisms regulating the reward system in the mesolimbic/mesocortical pathway (from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) and or the prefrontal cortex (PFC)). Information on new targets that the consumption of different abuse substances may modify is critical for developing pharmacological strategies.

The Endocannabinoid System: Role in SUD

ECS is a ubiquitous lipid signaling system distributed throughout the organism that participates in multiple intracellular signaling pathways [4,5]. Cannabinoid receptors, endogenous ligands or endocannabinoids (eCBs), and their synthesizing and degrading enzymes are the main components of the ECS, present in the central and peripheral nervous system [6,7], and in many other peripheral tissues regulating distinct functions [8].

The CB1 cannabinoid receptor (CB1r) is the most abundant G protein-coupled receptor in the brain [9]. Physiological actions of endocannabinoids in the CNS are mediated by the activation of CB1r [10]. Its expression in the CNS is widespread and heterogeneous and have crucial roles regulating brain function and disease processes [11–13]. The CB2 cannabinoid receptor (CB2r) was initially considered as a peripheral cannabinoid receptor due to its high expression in the rat spleen [14] and leukocyte subpopulation in humans [15], participating in the regulation of the immune system [16]. The first findings identified the presence of CB2r in the CNS only under pathological conditions such as in senile plaques in Alzheimer’s disease [17], activated microglial cells/macrophages in multiple sclerosis,
spinal cord in amyotrophic lateral sclerosis [18] and in the vicinity of tumors [19]. However, Van Sickle and colleagues revealed that CB2r is expressed in neurons of the brainstem of mice, rats and ferrets under normal conditions [20]. This finding significantly increased the interest of CB2r in the regulation of brain function [21–25]. Interestingly, CB2r was detected not only in microglia [26] but also in neurons [25,27,28] and astrocytes [29].