To better understand how marijuana affects the body, an international research team created a three-dimensional, atomic-level image of the molecular structure that tetrahydrocannabinol, marijuana's active ingredient, activates in the brain.
It wasn't easy, however. At first, the researchers led by Laura Bohn, Alexandros Makriyannis, Raymond C. Stevens and Zhi-Jie Liu struggled with producing a crystal form of human cannabinoid receptor 1 while it was bound to AM6538, a stabilizing molecule that acts to block the receptor's functions.
When the researchers finally succeeded in recreating CB1 in crystal form, as well as gathering data, they observed that the cannabinoid receptor complex's structure revealed an expansive, complicated binding network made up of numerous sub-pockets and multiple channels connecting to various parts of the receptor.
Cannabinoid receptors like CB1 are included in a large class of receptors called G protein-coupled receptors. Receptors of this type represent about 40 percent of all prescriptions in the market today and play crucial roles in several physiological functions.
When an external substance is bound to a GPCR, a G protein within the cell is activated, releasing components and creating a specialized cellular response. As an inverse agonist/antagonist bound tightly to CB1, AM6538 has a long half-life, which makes it promising as a possible treatment for addiction disorders.
"As marijuana continues to become more common in society, it is critical that we understand how it works in the human body," said Liu.
New insights into CB1 will offer a better understanding of why some THC-related molecules have unexpectedly complex and sometimes adverse effects. The results of future research using CB1's 3D model may impact the development of drugs for inflammation, fibrosis, obesity, pain and other conditions.
Published in the journal Cell, the study received funding support from the GPCR Consortium, ShanghaiTech University, the Shanghai Municipal Government, National Science Foundation, National Institutes of Health, National Nature Science Foundation of China and the Ministry of Science and Technology of China.
Earlier in September, another study was released, this time exploring the long-term effects of marijuana use on the brain. It has long been established that using marijuana affects the brain but the researchers discovered that exact effects may depend on how long marijuana was used and the age at which cannabis was first consumed.
Using MRI techniques, the researchers found that long-term marijuana users have a tendency to feature smaller orbitofrontal cortices, the brain region associated with addiction. However, these same users have more brain connections, suggesting that the body may be compensating for losses in gray matter by increasing functional and structural connectivity.
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