Evaluating the preclinical validity of cannabinoid therapy for the treatment of psychostimulant use disorder

Abuse of psychostimulants, including cocaine, methamphetamine, and amphetamines, is a global health problem, yet despite decades of research, there are no approved pharmacotherapies to help individuals cease or reduce their psychostimulant use. The endocannabinoid system is a potential a treatment target for psychostimulant use disorder. Here we review recent advances using preclinical models in targeting endocannabinoid enzymes, ligands, and receptors to reduce psychostimulant use and relapse. We review the impact of the cannabinoid ligands anandamide and 2-arachidonoylglycerol (2-AG), modulators of the cannabinoid enzymes fatty acid amide hydrolase (FAAH), diacylglycerol lipase (DAGL), and monocylglycerol lipase (MAGL), as well as cannabinoid 2 (CB2) receptor agonists and antagonists, on brain function and behavior for cocaine, methamphetamine, and amphetamine. We find that increasing anandamide levels reduces addiction-relevant behaviors for psychostimulant drugs, while decreasing the 2-AG levels inhibits cocaine-seeking behaviors. Increasing CB2 receptor signaling also reduces cocaine administration and cocaine-seeking. Together, this provides preliminary support for modulation of the endocannabinoid system to reduce psychostimulant abuse, in particular cocaine abuse.