Personalized medicine can pave the way for the safe use of CB1 receptor antagonists

Antagonists of cannabinoid type-1 (CB1) receptors have been explored as therapeutic agents for obesity and addiction. However, use of rimonabant (the first marketed CB, receptor antagonist) has been suspended due to its anxiogenic and depressive side effects (including suicide risk). Recent genomic studies provide evidence that variants of the CB1 receptor gene (CNR1) alone or in combination with the gene of the serotonin transporter (SLC6A4) contribute to the development of anxiety and/or depression, suggesting that high-risk individuals could be identified through genetic testing. In this review, we argue that identification of high-risk individuals by a combination of genomic screening, previous risk phenotype, and environmental risk factors offers a promising method for the safe use of centrally acting CB1 receptor antagonists. We summarize endocannabinoid signaling in pathways related to anxiety and depression, identify the serotonergic system as the most likely candidate to mediate the side effects of CB1 receptor antagonists, and propose that poloymorphisms in CNR1, SLC6A4 and certain CYP 450 enzymes could help to identify individuals who may benefit from treatment with CB(1)receptor antagonist without psychiatric side effects.