From Cannabinoid genomics to medical marijuana

ONAIVI E, ISHIGURO H, LIU QR, TAGLIAFERRO AP, BRUSCO A, GU S, UHL G.

San Diego

Congreso; 40 Annual Meeting Society for Neuroscience; 2010

Society for Neuroscience

Cannabinoids are the active constituents in marijuana, while endocannabinoids (eCBs), the natural, endogenous marijuana - like substances found in animals and humans are a component of an elaborate and ubiquitous endocannabinoid system (ECS). The ECS consist of eCBs, their degrading enzymes, fatty acid amide hydrolase (FAAH), and monoglyceride lipase (MGL), cannabinoid receptors (CBRs) - CB1-Rs and CB2-Rs. A major break-through in marijuana - cannabinoid research was the discovery that specific genes in human chromosome 6 and 1 encoding CB1-Rs and CB2-Rs respectively are activated by eCBs, cannabinoids and marijuana use. We used immunoblotting, genotyping, immunoelectron microscopy, mouse behavioral assessment and quantified human and rodent CB2-R specific isoforms in different tissues and brain regions as well as in mice treated with cannabinoid ligands to investigate the neuronal functional role of CB2-Rs in the brain. Association studies were performed between CB2-R SNPs in schizophrenia, depression, eating disorders and alcoholism in a human population. There is an increased risk of schizophrenia for people with low CB2 receptor function. Naïve BTBR mice that have been reported to have autism-like behavioral phenotypes have an upregulated high level of CB2A gene expression in the cerebellum. Indeed our studies provide the first evidence for neuronal CNS effects of CB2-Rs and its possible involvement in drug addiction and other neuropsychiatric disorders. The genes encoding the components of the ECS and their gene products are major therapeutic targets in many disorders. As cannabinoid receptors are encoded in our genes, cannabinoid pharmacogenomics hold promise in disorders associated with genetic risk factors in the endocannabinoid system. Much progress in cannabinoid genetics is providing genetic variants and mutations in the endocannabinoid system, that deepen our understanding of cannabinoid pharmacogenomics. Thus, with the promise of personalized medicine, the availability of cannabinoid pharmacogenomic tests can be utilized to determine an individual’s response to cannabis which will allow individually tailored cannabinoid therapies that target the different components of the endocannabinoid system. Support NIDA-NIH, WPUNJ.