Chronic pain is a pervasive condition affecting millions of individuals worldwide, and in the United States alone, it impacts an estimated 50 million people. For many of these individuals, opioids have long been the standard treatment for pain management. While opioids are effective at dulling pain, they come with a significant downside: they are highly addictive and can lead to fatal overdoses if misused. In fact, the opioid epidemic in the U.S. has resulted in the loss of tens of thousands of lives each year, with approximately 82,000 deaths attributed to opioids in 2022 alone. This grim reality has prompted a search for alternative pain management options—ones that could offer the same level of relief without the addictive and life-threatening risks associated with opioids.
In a significant breakthrough, researchers at Washington University School of Medicine in St. Louis and Stanford University have developed a novel compound that holds great promise in addressing the challenges of chronic pain relief. This compound mimics the pain-relieving properties of cannabinoids, the natural molecules found in the cannabis plant, without causing the mind-altering side effects or addiction typically associated with cannabis. The study, which was published in Nature, marks an important step forward in the quest to develop non-addictive, effective pain treatments.
The senior author of the study, Dr. Susruta Majumdar, Ph.D., a professor of anesthesiology at WashU Medicine, has been focused on finding non-addictive pain relief solutions for the past 15 years. “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,” Dr. Majumdar stated. The compound developed in the study is a custom-designed cannabinoid molecule that attaches to pain-reducing receptors in the body. However, the key innovation is that it has been specifically designed to prevent it from crossing the blood-brain barrier, which means it doesn’t interact with the brain. This eliminates the risk of psychoactive side effects, such as mood changes, and prevents the compound from triggering the brain’s reward system, which is responsible for addiction.
In contrast, opioids act directly on the brain’s reward system, releasing dopamine and creating feelings of euphoria, which make them highly addictive. Despite the widespread public health campaigns and warnings surrounding the dangers of opioid addiction, the number of opioid-related deaths continues to rise. This underscores the need for new pain relief options that can effectively treat chronic pain without these dangerous side effects.
Cannabis has long been used as a natural remedy for pain, but its psychoactive effects, driven by the cannabinoid molecules it contains, have limited its practical application in pain management. Cannabis works by binding to a receptor known as cannabinoid receptor one (CB1), which is found not only in the brain but also in pain-sensing nerve cells throughout the body. This binding is responsible for both the pain-relieving effects and the mind-altering experiences that are commonly associated with cannabis use. Researchers have long sought ways to harness the beneficial effects of cannabinoids while mitigating their psychoactive properties.
The breakthrough compound developed by the researchers at WashU Medicine and Stanford University represents a major leap forward in this area. Collaborating with Dr. Robert W. Gereau, Ph.D., the director of the WashU Medicine Pain Center, the team designed a synthetic cannabinoid with a positive charge, which prevents it from entering the brain. This modification allows the compound to interact with the CB1 receptors on pain-sensing nerve cells located outside the brain, providing pain relief without causing the mind-altering effects that would typically occur with cannabis use.
The research team, led by Dr. Vipin Rangari, Ph.D., a postdoctoral research associate at WashU Medicine, tested the modified cannabinoid compound in animal models, specifically in mice that were induced with nerve-injury pain and migraine-like headaches. To assess the pain response, researchers used a technique that involves applying a normally non-painful stimulus to measure hypersensitivity to touch. In both of these models, the mice exhibited reduced hypersensitivity to touch after receiving injections of the modified compound, indicating that the compound successfully alleviated pain without the side effects commonly associated with traditional pain medications like opioids.
Another significant challenge with many pain relievers, including opioids, is the development of tolerance over time. As individuals use the medication, they may require higher and higher doses to achieve the same level of pain relief, leading to the risk of dependence and overdose. In contrast, the compound developed in this study showed no signs of tolerance, even after repeated use. Mice that received the compound twice a day for nine consecutive days continued to experience effective pain relief, a promising sign that the compound may be suitable for long-term treatment without the risk of diminished efficacy.
This lack of tolerance is due to the bespoke design of the cannabinoid molecule. The researchers employed sophisticated computational modeling to identify a previously overlooked binding site on the CB1 receptor. This “hidden pocket” allows the modified cannabinoid to bind in a way that reduces the cellular activity associated with developing tolerance. While the binding site had previously been considered inaccessible to cannabinoids, the researchers discovered that it opens briefly under certain conditions, providing a novel way for the compound to interact with the receptor and avoid the development of tolerance.
Designing molecules that can relieve pain without causing undesirable side effects or addiction is an incredibly challenging task, but the work done by the team at WashU Medicine and Stanford University has taken an important step toward overcoming these hurdles. The success of their custom-designed cannabinoid compound in mouse models paves the way for further research and development of this treatment, with the potential for creating a non-addictive, long-lasting pain reliever for chronic pain sufferers.
Looking forward, the researchers plan to refine and further develop the compound into an oral medication that could eventually be evaluated in clinical trials. If successful, this new pain reliever could offer a much-needed alternative to opioids and other pain medications, providing an option for the millions of individuals who live with chronic pain and struggle to find effective, non-addictive treatments.
The significance of this research cannot be overstated. As the opioid crisis continues to claim lives and devastate families, finding safer alternatives to traditional painkillers has become an urgent priority. This new compound, with its targeted approach and absence of psychoactive side effects, represents a potential breakthrough in the treatment of chronic pain—offering hope for those who have long suffered from the debilitating effects of conditions like nerve injury pain and migraines.
The work conducted by Dr. Majumdar and his colleagues is a powerful reminder of the importance of scientific innovation in addressing public health crises. As the world continues to grapple with the opioid epidemic, solutions that can offer effective, non-addictive pain relief are not just desirable—they are essential. The promise of this cannabinoid-inspired compound is a step toward achieving that goal, and while further research is needed, it is a hopeful sign that the future of pain management could look significantly different from the past.
More information: Susruta Majumdar, A cryptic pocket in CB1 drives peripheral and functional selectivity, Nature (2025). DOI: 10.1038/s41586-025-08618-7. www.nature.com/articles/s41586-025-08618-7