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CNS Drugs

, Volume 33, Issue 10, pp 1001–1030 | Cite as

Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders

  • Ewa Galaj
  • Zheng-Xiong XiEmail author
Review Article

Abstract

Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited. During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids. Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008. Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs. In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs. As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆9-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals. Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.

Notes

Compliance with Ethical Standards

Funding

This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, USA.

Conflict of interest

Ewa Galaj and Zheng-Xiong Xi have no conflicts of interest that are directly relevant to the content of this article.

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Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Addiction Biology Unit, Molecular Targets and Medication Discoveries Branch, Intramural Research ProgramNational Institute on Drug AbuseBaltimoreUSA

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