Drug addiction is a major health and social issue in most contemporary societies (WHO, 2020). According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), it is characterized by the loss of inhibitory control and compulsive drug intake regardless of the long-term deleterious impact [1]. Long-term drug consumption results in molecular modifications in several brain areas, such as the mesolimbic system, amygdala, hippocampus, and prefrontal cortex [2, 3], which result in behavioral responses of binge and intoxication followed by withdrawal and negative affect, preoccupation and craving. All these neurochemical and behavioral modifications often lead to relapse and the inability to quit drug use [4, 5]. Currently, few medications can efficiently treat compulsive drug intake, withdrawal symptoms, and relapse [6]. Thus, preclinical research has been focusing on new strategies for pharmacologically targeting the brain reward system and related circuits disrupted in addiction [7]. Among these new potential targets is the endocannabinoid system (eCBS). The eCBS may be involved in various aspects of drug addiction, including reward, contextual memories precipitating drug seeking, drug tolerance, and withdrawal effects [8, 9]. The eCBS comprises two main cannabinoid receptor subtypes (CB₁R and CB₂R), their endogenous ligands, termed endocannabinoids, and the proteins and enzymes responsible for endocannabinoid transport, biosynthesis, and degradation [10]. CB₁R are densely expressed throughout brain regions related to reward and drug addiction [10-13], where they modulate the dopaminergic mesolimbic circuit and drug-associated reward [14]. Accordingly, CB₁R antagonism reduces dopamine release in the mesolimbic pathway, possibly by disinhibiting GABAergic afferent neurons projecting onto the ventral tegmental area (VTA) and nucleus accumbens [15]. As such, much effort was put into the development of CB₁R modulators and their investigation of drug-related responses. In fact, CB₁R antagonists and inverse agonists, such as rimonabant, taranabant, surinabant, and AM251, show robust effects in inhibiting drug-induced behaviors [15-17]. Unfortunately, however, the enthusiasm for these drugshas been dumped by the occurrence of clinically significant psychiatric side effects [18]. Contrary to CB₁R, CB₂R were initially considered a peripheral receptor, absent from neurons in the central nervous system [18, 19]. As a result, initial pharmacological studies focused on CB₂R agonists primarily as analgesic drugs devoid of central side effects. Later on, evidence from histological, genetic, electrophysiological, and pharmacological approaches challenged the view of CB₂R as a “peripheral receptor”. CB₂R were identified in neurons in specific brain regions, including those involved in addiction, such as the midbrain VTA neurons [20-23]. In this pathway, CB₂R expression occurs in the cell bodies of dopaminergic neurons [20, 21]. Moreover, their pharmacological activation counteracts the dopamine release in the nucleus accumbens induced by drugs of abuse [20]. CB₂R agonists prevent drug reward [17, 24] and reduce the reinforcing effects of cocaine and ethanol [25-27]. In addition, CB₂R knockout mice were more likely to develop ethanol-induced conditioned place preference (CPP), higher sensitivity to withdrawal after the ingestion of acute doses of ethanol, and higher ethanol intake in comparison to wild type control group [28]. Thus, CB₂R activation could represent a novel mechanism for drug addiction treatment. Moreover, CB₂R agonists do not induce the psychiatric side effects related to the blockade of CB₁R. In fact, they reduce anxiety-like behaviors in rodents [29]. This review aims to discuss the effects of a CB₂R agonist, the compound (1R,9S,E)-4,11,11-Trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene, β-caryophyllene (BCP). BCP is a natural bicyclic sesquiterpene found in Cannabis and other plants [29, 30]. It was approved as a food additive and classified as “generally recognized as safe” by the Food and Drug Administration (FDA). As a terpenoid, the synergistic interaction between BCP and eCBS is presumed to result in important pharmacological properties and therapeutic potential [31]. BCP acts as a CB₂R agonist with an insignificant affinity towards CB₁R [31, 32]. As such, its administration seems to be devoid of abuse potential [31-33] and of psychotropic side effects related to CB₁R binding [34]. In addition, preclinical results have shown that BCP induces anxiolytic, antidepressant [29], and analgesic effects [35]. Moreover, BCP has been investigated regarding its ability to counteract the effects of drugs of abuse [32, 36]. This paper will review preclinical studies investigating the potential use of BCP for the treatment of substance use disorders and discuss the involvement of CB₂R in such responses.