Pain Relief Research: Clearing the Smoke Surrounding Cannabis

Cannabis: It’s a topic surrounded by controversy. In the United States, public opinion and politicians have long grappled with the legal, ethical and societal implications of its use. What regulations are needed? Is it addictive? Is it safe? Only recently have scientists begun to unravel the mysteries of Cannabis sativa, a plant that is cultivated for food, fiber and, in every part of the world, medicinal use.

At the University of Arizona Health Sciences, researchers are expanding the scientific knowledge of cannabis with a focus on two distinct areas: pain and addiction. Leading the way is Todd Vanderah, Ph.D., director of U of A Health Sciences Comprehensive Center for Pain & Addiction. Vanderah has spent two decades studying cannabinoids, the compounds found in cannabis.

“I’ve worked at seeking to understand chronic pain for many years, trying to figure out how we could develop new compounds to help people with pain that weren’t opiates and weren’t addictive. One of the areas we began to explore was cannabinoids,” says Vanderah, Regents Professor and head of the Department of Pharmacology at the College of Medicine – Tucson.

Cannabis contains about 540 chemical compounds. THC, or tetrahydrocannabinol, is the cannabinoid responsible for the plant’s psychoactive effects and has been the focus of much research through the years. CBD, or cannabidiol, has a chemical structure slightly different than THC. It doesn’t produce psychoactive effects, and little is known about its activity.

Even less is known about other cannabinoids and other parts of the plant, such as terpenes, which give cannabis its distinctive aroma and taste.

‘We are only just beginning to understand all of the different chemicals that are naturally present in cannabis. ... I’m probably the most excited about understanding the endocannabinoid system.’

“We are only just beginning to understand all of the different chemicals that are naturally present in cannabis,” says Vanderah, who is a member of the BIO5 Institute. “I’m probably the most excited about understanding the endocannabinoid system.”

Those are the cannabinoids that the human body makes.

Most people know endorphins cause the “runner’s high” often experienced by athletes. Endorphins are the body’s endogenous, or naturally occurring, opioids. Once produced, endogenous opioids activate receptors that produce physiological changes such as pain relief.

Exogenous opioids, those that are not naturally produced and originate from outside the body, work by co-opting the endogenous opioid system. Prescription drugs, such as Oxy-Contin, target and activate opioid receptors. Once activated, the receptors produce the same result as endorphins: pain relief.

In a similar fashion, the body produces endogenous cannabinoids. While scientists have been studying the endogenous opioid system since the 1970s, research into the endogenous cannabinoid system, or endocannabinoid system, is still in its infancy. Researchers know endocannabinoids play a role in maintaining cellular balance, and many believe the endocannabinoid system also helps regulate functions such as mood, appetite and sleep.

“Our bodies make cannabinoids, and we make plenty of them,” says Vanderah. “A number of studies have shown that physical exercise increases the amount of endocannabinoids in circulation, just like endorphins. One review pointed out that stress can release endocannabinoids, and the increased levels of endocannabinoids may actually decrease some of that stress.”

Early cannabinoid research has identified two cannabinoid receptors and enzymes that make and break down endocannabinoids. The receptors, dubbed CB1 and CB2, are located throughout the body, including in the central and peripheral nervous systems.

“CB1 is interesting in that some people suggest it’s the highest concentrated receptor in the human brain, and we know that compounds that act at the CB1 receptor will produce psychotropic effects,” says Vanderah, who has directed much of his research at the lesser-studied CB2 receptor.

“CB2 receptors are found more on immune cells, and they tend to be on the immune cells of the bones, spleen, colon, liver and pancreas.

“We know there are CB1 and CB2 receptors functioning in many parts of the body. For ex-ample, we know there are a lot of receptors in the lungs,” Vanderah adds, “but we don’t know what they are doing there. There is a lot of research that needs to be done.”

With many of the internal mechanisms of the endocannabinoid system identified, researchers are seeking to understand how specific cannabinoids act on those mechanisms, whether changes in the endocannabinoids are related to disease states, and how the endocannabinoid system can be modulated to develop new treatments for pain and inflammation.

To that end, much of the University of Arizona’s endocannabinoid research focuses on two areas: substances that may act as CB1 and CB2 agonists, meaning they activate the receptors, and enzyme modulators that would alter levels of endocannabinoids. 

Recreational use of cannabis is legal in 24 states, with an additional 14 states allowing for medicinal use only. Still, cannabis remains a Schedule I drug, making it challenging for researchers to access and study. That might change, as the DEA and Department of Justice recently recommended reclassifying it as a Schedule III — or “moderate to low potential for physical and psychological dependence” — drug, opening up new paths for research and patient care.