title: Personalized medicine can pave the way for the safe use of CB₁ receptor antagonists.
abstract: Antagonists of cannabinoid type-1 (CB₁) receptors have been explored as therapeutic agents for obesity and addiction. However, use of rimonabant (the first marketed CB₁ 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 CB₁ receptor antagonist without psychiatric side effects.
authors.affiliation: Kutvolgyi Clinical Centre, Semmelweis University, Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Lazary
authors.forename: Gabriella
authors.initials: G
authors.lastname: Juhasz
authors.forename: Laszlo
authors.initials: L
authors.lastname: Hunyady
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bagdy
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000494:pharmacology; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D009765:Obesity / Q000188:drug therapy; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology; D011110:Polymorphism, Genetic; D057285:Precision Medicine / Q000379:methods*; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D019966:Substance-Related Disorders / Q000188:drug therapy
chemical_list: D019440:Anti-Obesity Agents; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant