Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms

Abstract

Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- and stress-induced reinstatement of cocaine and priming-induced reinstatement of METH seeking behaviours. CBD also potentiated the extinction of cocaine- and amphetamine-induced conditioned place preference (CPP), impaired the reconsolidation of cocaine CPP and prevented priming-induced reinstatement of METH CPP. Observational studies suggest that CBD may reduce problems related with crack-cocaine addiction, such as withdrawal symptoms, craving, impulsivity and paranoia (Fischer et al., 2015). The potential mechanisms involved in the protective effects of CBD on addiction to psychostimulant drugs include the prevention of drug-induced neuroadaptations (neurotransmitter and intracellular signalling pathways changes), the erasure of aberrant drug-memories, the reversion of cognitive deficits induced by psychostimulant drugs and the alleviation of mental disorders comorbid with psychostimulant abuse. Further, preclinical studies and future clinical trials are necessary to fully evaluate the potential of CBD as an intervention for cocaine and methamphetamine addictive disorders.

Keywords: addiction; cannabidiol; cocaine; conditioned place preference; methamphetamine; mice; rat; reinstatement; reward; self-administration.

Figure 1

Components of cannabinoid synapsis modulated by CBD (★). The two main endocannabinoids (EC), anandamide (AEA) and 2-arachidonylglicerol (2-AG), are synthesized in the post-synaptic nerve terminal. AEA is produced by hydrolysis of N-arachidonyl phosphatidylethanolamine (NAPE) which is catalized by the enzyme phospholipase D (PLD). 2-AG is produced by the metabolism of diacylglicerol (DAG) by specific diacylglicerol lipases (DAGL). These EC act mainly through cannabinoid CB1 and CB2 receptors, although other receptors have been identified as targets of EC including a non-cloned CB3 receptor, GPR3, and the peroxisome proliferator activated-receptor gamma (PPARg). EC function as retrograde signalling molecules that inhibit the release of classical anterograde neurotransmitters (NT) by presynaptic terminals and binding with their receptor (NT receptor, NTR). After the activation of presynaptic CB1 receptors (by AEA or 2-AG), different signal transduction mechanisms are stimulated via G inhibitory proteins. EC reduce activity of protein kinases, as mitogen-activated protein kinase (MAPK), modulate ion channels (stimulation of potassium and inhibition of calcium channels) and inhibit NT release. The activity of endocannabinoids is limited by a transporter (AT) that reuptakes AEA and 2-AG into the post-synaptic cell. AEA is degraded by the enzyme fatty acid amidohydrolase (FAAH) and 2-AG is degraded by the enzime monoacylglicerol lipase (MAGL). CBD has been demonstrated to modulate anandamide signalling, CB1 and CB2 receptors, GPR3 and PPARg receptors and the activity of the enzymes FAAH and MAGL.

Figure 2

Hypothetical mechanisms involved in the effects of CBD on cocaine/METH addiction. The involvement of these processes is supported by the results of preclinical studies. VTA: ventral tegmental area; DA: dopamine; NAcc: nucleus accumbens; DA D2: dopamine D2 receptors; CB1R; cannabinoid receptors type 1; Hipp: hippocampus; CB2R; cannabinoid receptors type 2; vmPFC: ventromedial prefrontal cortex; m-OR: mu opioid receptors; d-OR: delta opioid receptors; 5-HT: serotonin; 5-HT1AR: type 1A serotonin receptors; 7-nAChR: nicotinic acethylcholine receptors type 7; GSK3: glycogen synthase kinase-3; Akt: protein kinase B; mTORC1: mammalian target of rapamycin complex 1; MAPK, mitogen-activated protein kinase; ERK1/2: Extracellular signal-regulated kinases type 1 and type 2; BDNF: brain derived neurotrophic factor; TrkB: Tropomyosin receptor kinase B; Amyg: amygdala; mPFC: medial prefrontal cortex; IL: interleukine; TNF- α: tumor necrosis factor alpha; PPARg: Peroxisome proliferator-activated receptor gamma.