Chronic pain affects nearly 50 million Americans, and for decades, opioids have been the primary treatment despite their addictive nature and deadly risks. Now, researchers at Washington University School of Medicine in St. Louis and Stanford University have developed a novel compound inspired by the cannabis plant that offers pain relief without addiction or psychoactive side effects.
Published in Nature, the study highlights a synthetic molecule designed to engage cannabinoid receptor one (CB1) outside the brain, bypassing the reward system that makes opioids so addictive. The breakthrough could mark a significant step forward in nonaddictive pain management.
Dr. Susruta Majumdar, a professor of anesthesiology and senior author of the study, emphasized the urgency of developing safer pain treatments. “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.”
Cannabis has long been recognized for its pain-relieving properties, but its psychoactive effects limit its medical use. The mind-altering effects come from cannabinoid molecules that bind to CB1 receptors in the brain and nervous system. The researchers overcame this issue by designing a positively charged synthetic cannabinoid molecule that cannot cross the blood-brain barrier. This allows it to activate CB1 receptors outside the brain, offering pain relief without the high.
Tests in mice showed that the compound effectively reduced pain in models of nerve injury and migraines. Unlike opioids, which often require escalating doses due to tolerance, the new compound maintained its effectiveness over a nine-day trial with no signs of tolerance development.
A key aspect of this discovery was the identification of a previously inaccessible “hidden pocket” on the CB1 receptor. Using computational modeling, the Stanford team found that this pocket temporarily opens, allowing the modified cannabinoid to bind in a way that minimizes tolerance.
While more research is needed, the team aims to develop an oral medication based on this discovery and advance to clinical trials. This breakthrough could transform pain management by offering an effective, nonaddictive alternative to opioids, potentially revolutionizing treatment for millions suffering from chronic pain.
Read the full study in Nature: https://www.nature.com/articles/s41586-025-08618-7