Scientists have developed a new compound to harnesses the pain-relieving properties of cannabis without any unwanted side effects, pointing to a possible alternative to opioids. 

In the search for alternative pain relievers, researchers at Washington University School of Medicine in St. Louis and Stanford University have developed a compound that mimics a natural molecule found in the cannabis plant.

In an animal study, published in the journal Nature, the compound was found to demonstrate the pain-relieving properties without causing addiction or any mind-altering side effects.

The researchers say that while more studies are needed, the compound shows promise as a nonaddictive pain reliever that could help the estimated 50 million people in the U.S. suffering from chronic pain.

Opioids dull the sensation of pain in the brain and hijack the brain’s reward system, triggering the release of dopamine and feelings of pleasure, which make the drugs so addictive. 

Despite widespread public health warnings and media attention focused on the dangers of opioid addiction, numerous overdose deaths still occur, with some 82,000 deaths in the U.S. linked to opioids in 2022.

‘Custom-designed’ cannabis compound

The cannabis plant produces natural cannabinoids which bind to CB1 receptors on the surface of brain cells and on pain-sensing nerve cells throughout the body.

Working with collaborators at Stanford University, co-first author Vipin Rangari, PhD, a WashU Medicine postdoctoral research associate in Majumdar’s laboratory, designed a cannabinoid molecule with a positive charge, preventing it from crossing the blood-brain barrier into the brain while allowing the molecule to engage CB1 receptors elsewhere in the body. 

By modifying the molecule such that it only binds to pain-sensing nerve cells outside of the brain, the researchers achieved pain relief without mind-altering side effects.

They tested the modified synthetic cannabinoid compound in mouse models of nerve-injury pain and migraine headaches, measuring hypersensitivity to touch as a proxy for pain. In both mouse models, injections of the modified compound eliminated touch hypersensitivity.

The compound illustrated here in cyan, nestled within a protein (green and purple) involved in sensing pain. Photo credit: Tasnia Tarana

The study’s senior author Susruta Majumdar, PhD, a professor of anesthesiology at WashU Medicine, commented: “There is an urgent need to develop nonaddictive treatments for chronic pain, and that’s been a major focus of my lab for the past 15 years.

“The custom-designed compound we created attaches to pain-reducing receptors in the body but by design, it can’t reach the brain. This means the compound avoids psychoactive side effects such as mood changes and isn’t addictive because it doesn’t act on the brain’s reward center.”

Prolonged pain relief

For many pain relievers, particularly opioids, tolerance to the medications over time can limit their long-term effectiveness and require higher doses of medication to achieve the same level of pain relief. 

In this study, the modified compound offered prolonged pain relief – the animals showed no signs of developing tolerance despite twice-daily treatments with the compound over the course of nine days. 

The researchers believe this resulted from the bespoke design of the compound. 

This is a promising sign, the researchers say, that the molecule could be used as a nonaddictive drug for relief of chronic pain, which requires continued treatment over time.

“For millennia, people have turned to marijuana as a treatment for pain,” added co-corresponding author Robert W. Gereau, PhD, the Dr. Seymour and Rose T. Brown Professor of Anesthesiology and director of the WashU Medicine Pain Center. 

“Clinical trials also have evaluated whether cannabis provides long-term pain relief. But inevitably the psychoactive side effects of cannabis have been problematic, preventing cannabis from being considered as a viable treatment option for pain. However, we were able to overcome that issue.”

They now plan to further develop the compound into an oral drug that could be evaluated in clinical trials.