This X-ray image of CB 1's crystal structure is the first step in understanding why THC affects the humans brain.
This X-ray image of CB 1's crystal structure is the first step in understanding why THC affects the humans brain.
Courtesy Stevens Laboratory, USC

Scientists Closer to Understanding Why Weed Gets Us High

Scientists are getting closer to understanding how marijuana gets people high, thanks to new X-ray images of an ornery protein that has eluded researchers for years. The recent passage of loosened marijuana regulations will also allow more scientists to study the substance.

Cannabinoid receptor 1, or CB1, is an unstable protein located in the central and peripheral nervous system, which interacts with THC to produce a psychoactive effect. CB1 has remained particularly elusive due to its very nature. It is just one of 826 G-protein–coupled receptors found in the human body that carries out important cellular functions, such as communicating between cells and their surrounding environments. When GPCRs malfunction, internal anarchy ensues and can result in cancer, diabetes and even mental health disorders. Understanding more about this particular class of receptors can help scientists develop new medicines, including those that are cannabis-based, to help treat these potential fatal conditions. Learning more about CB1 can also help scientists figure out which properties make synthetic marijuana, or spice, so deadly. Spice even caused some serious health problems for L.A.'s Skid Row residents recently.

The road to understanding CB1 started about 10 years ago, when California-based scientist Michael Hanson first worked with a team of students to glean new information regarding GPCRs, whose unstable properties made them nearly impossible to X-ray. Digitizing images of their structure is key to learning how they function, but in order to snap an X-ray, these proteins have to remain still long enough to capture their image. That’s where scientists got stuck 10 years ago.

“It just didn’t behave very well,” Hanson says. “It was really interesting, but we just couldn’t make any progress on it.”

Fast-forward to today and Hanson’s new team, including scientists from the University of Southern California, University of California at San Diego, Northeastern University in Boston and ShanghaiTech University in Shanghai, China, has finally made inroads in shooting images of the pesky CB1.

“We came up with the right combination of tricks that we can pull out of our repertoire and get this to work,” he says.

Their proverbial bag of tricks included extracting the protein’s DNA and implanting it inside a different organism. Scientists were first able to access CB1 through a strain of insect cells and later through Chinese hamster cells.

“Knowing where to look was part of the magic in this case,” Hanson says.

Once scientists isolated the protein, they put it back into an artificial membrane system for crystallization. This forced the protein to bind with nearby cells and form a repeating lattice similar to a diamond or gemstone. After the protein crystallized, researchers could finally X-ray its structure and begin the long road to understanding how this protein reacts in various situations. But getting them to crystallize in the first place took several years of trial and error.

“These proteins are very complicated and don’t want to be in the crystals, they want to be in their native membranes,” explains Irina Kufavera, a computational biologist from UCSD, who worked with Hanson on CB1. “Once [the receptors] are in crystals, you have to get them to stay very still in rows and columns like soldiers, and they don’t want to do that. They just want to lay down and die on you. Engineering the proteins and designing the right ligands was key to success.”

Now that scientists can see the structure of these crystals, they can start to study the atomic structure of individual brain receptors and how they will interact in different scenarios, including THC.

“The benefits of understanding how marijuana elicits its effects on a molecular level will not only help us understand why it works so well and what additional conditions it can be used for,” Hansons says. “It can also help us try to develop more potent alternatives that may not have the associated side effects, which are in this case not just pharmacological but societal and regulatory, as well.”

At the same time Hanson was studying CB1 and other G-proteins, so-called “reverse marijuana” pharmaceuticals were already hitting the European market and promising to curb appetite in severely overweight people. By 2006, an anti-obesity drug called Rimonabant was approved for sale by the European Commission. It blocked CB1 but came with disastrous side effects, including depression and anxiety. Sales of the drug never made it to the States, and they were banned altogether in 2009.

As scientists continue to study CB1, they are also getting closer to figuring out why humans can die from spice but not the natural marijuana. It’s a conundrum that continues to vex researchers because brain reactions to marijuana can vary wildly depending on the strain, strength and even person.

“Really, it’s a very interesting case of nature developing something that is nowhere near as dangerous as what humans can come up with,” Hanson notes.

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