Exogenous cannabinoids: Δ9-THC vs. CBD
Cannabis is the world’s most commonly used illicit drug (159, 160). Between 119 and 224 million people are cannabis users worldwide (4). Cannabis contains over 85 different chemical substances unique to the plant and termed phytocannabinoids. Among them, Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the two main components of cannabis, which has been used for thousands of years for both recreational and medicinal purposes. Most studies regarding cannabis properties have focused on Δ9-THC, which is the main psychoactive constituent in cannabis extracts (161). Although Δ9-THC possesses a number of therapeutic effects (e.g., on pain, spasms, inflammation), its negative impact on the CNS has been highlighted in several clinical studies on subjects smoking cannabis, documenting impulsive behavior, cognitive impairment, consumption of addictive substances, and psychiatric disorders (e.g., schizophrenia, depression, and anxiety) (162– 165). For example, Δ9-THC has been shown to induce psychotic-like and anxiogenic effects when administered intravenously to healthy subjects (166, 167). Other experimental studies revealed that Δ9-THC injection in animal models causes hypolocomotion, catalepsy, antinociception, and hypothermia (168).
Pharmacological studies in animal models suggest that not all therapeutic effects related to cannabis administration can be ascribed to Δ9-THC [reviewed in Ref. (169)]. Indeed, CBD – the second most abundant cannabinoid found in cannabis – acts as an antidepressant and possesses anticonvulsant, antiemetic, anxiolytic, and sleep-promoting as well as neuroprotective properties in humans (160, 170–176). CBD mediates its neuropharmacological properties by acting as an inverse agonist on CB1 and CB2 receptors (177, 178); it also stimulates the TRVP1 and TRVP2 (179) which serve as so-called ionotropic cannabinoid receptors. In addition, CBD inhibits FAAH, the main catabolic enzyme that alters the hydrolysis of the endogenous cannabinoid neurotransmitter AEA (180) (see above section), and is also an antagonist at the putative GPR55 receptor. The clinical association of the modulation of the ECBS by CBD remains to be fully investigated; this effect could arguably be related to DA uptake inhibition (181). Interestingly, ECBS interacts closely with other neurobiological structures which are implicated in the neural adaptations observed during chronic use of drugs and vulnerability to addiction. For example, CBD plays a role in the modulation of extracellular levels of DA (182) as well as μ and δ opioid receptors (183); it increases adenosine signaling through inhibition of uptake (184). Moreover, μ opioid and CB1 receptors colocalized within neural regions are known to modulate reward, goal-directed behavior, and habit formation relevant to addiction including striatal output projection neurons of the NAc and dorsal striatum (185, 186). While further studies are required to better understand the impact of CBD on GLU neurotransmission, its protective effects on GLU toxicity (187) and its psychopharmacologic interaction with ketamine (188), a N-methyl-d-aspartic (NMDA) receptor antagonist, are well documented. CBD activates also the serotoninergic receptors 5-HT1A (5-hydroxytryptamine) (171, 176, 189–193), which in turn diminishes vulnerability to stress and has anxiolytic-like effects in animal models (170, 172, 189, 190, 192–195). Similar results were observed in humans, where CBD administration decreases autonomic arousal and subjective anxiety (196). Interestingly, these anxiolytic effects have been linked to the modulation of core regions involved in the “emotional brain,” including limbic system structures such as the AMG and the ACC (197, 198). CBD’s anxiolytic effects were further confirmed by a study indicating that the effective connectivity between ACC and AMG is attenuated during the emotional processing of fearful faces, while resting activity of the left parahippocampus gyrus is increased. (196, 199). Remarkably, these neural structures are activated during drug craving in cocaine addiction (197, 200). It also decreases compulsive behaviors in rodents, which is hypothesized to be related to CB1-related mechanisms (201, 202).
While CBD has neuroprotective properties (187, 203, 204) and Δ9-THC administration have been shown to cause neurotoxic effects (205), these opposing properties have been highlighted in brain imaging studies where Δ9-THC and CBD activate different brain regions during tasks engaging verbal memory (206, 207), response inhibition (208), and emotional processing (196, 209–211). When given at appropriate doses, CBD counteracts Δ9-THC properties. Thus, CBD can modulate the functional effects of Δ9-THC (177, 178). Pre-clinical studies demonstrate that CBD decreases Δ9-THC-induced conditioned place aversion and social interaction of on operant behavior model (212, 213). In addition, CBD diminishes Δ9-THC-induced anxiety and psychotic-like symptoms in humans (214, 215). Together, this data clearly suggests that CBD limits Δ9-THC adverse effects. Thus, administered together, CBD might increase Δ9-THC clinical efficacy (216, 217). It has been established that unlike, Δ9-THC, CBD possesses therapeutic properties that could reduce withdrawal symptoms often present in individuals with addictive disorders (e.g., anxiety, psychotic, mood symptoms, insomnia, and pain). For example, a recent pre-clinical study from Hurd’s group aimed at assessing the effects of cannabinoids on opioid-seeking behaviors in rats indicates that while Δ9-THC potentiates heroin SA, CBD inhibits cue-induced heroin-seeking behaviors for up to 2 weeks following the last administration (218). In addition, CBD is well tolerated and has no gross effects on motor function (such as locomotor activity). CBD is also protects against damages caused by various substances; it reverses binge ethanol-induced neurotoxicity (219) and mitigates the cardiac effects of Δ9-THC (220, 221). Together this data illustrates the different, and sometimes opposite, neurobiological properties of the two main constituents of cannabis – CBD and Δ9-THC – that are linked to neural circuits which might play significant roles in addiction disorders. However, while numerous studies have highlighted the participation of the ECBS in the rewarding and addictive properties of drugs of abuse such as opioids, nicotine, and alcohol over the last decades, relatively few studies have focus on the impact of this system on addiction to psychostimulants.