Reducing Risk of Opioid Addiction While Alleviating Pain

Increasing the levels of chemicals naturally produced in the body called endocannabinoids may thwart the highly addictive nature of opioids such as morphine and oxycodone while maintaining the drugs’ ability to relieve pain, according to Weill Cornell Medicine investigators working with researchers from the Center for Youth Mental Health at NewYork-Presbyterian. Endocannabinoids bind to cannabinoid receptors throughout the body that regulate activities, such as learning and memory, emotions, sleep, immune response and appetite.

The preclinical study, published in Science Advances, may lead to a new type of therapeutic that could be taken with an opioid regimen to only reduce the rewarding aspect of opioids.

In 2023, opioid abuse or overuse was responsible for more than 80,000 deaths, according to the U.S. Centers for Disease Control and Prevention. “When someone has surgery and is taking opioids for pain management, there’s always a risk of developing a dependence on these drugs,” says senior author Dr. Francis Lee, chair of the Department of Psychiatry at Weill Cornell Medicine and psychiatrist-in-chief at New York-Presbyterian/Weill Cornell Medical Center.

Prior to this project, Dr. Lee’s work focused on the role of endocannabinoids in fear and anxiety. His co-author, Dr. Anjali Rajadhyaksha, adjunct professor of neuroscience research in pediatrics at Weill Cornell Medicine, studied cocaine addiction. They decided to work together when reports in the literature suggested that the opioid system could potentially interact with the endocannabinoid system’s complex network of chemicals and receptors.

Surprisingly, the findings upend the central dogma in the opioid field that combining endocannabinoids and opioids should exacerbate addictive behaviors in a synergistic way.

The researchers experimented with introducing a chemical called JZL184 that prevents 2-AG — one of two main endocannabinoids — from breaking down in the brain. They found that increasing 2-AG counteracts the rewarding properties of opioids, dampening behaviors associated with opioid addiction, while still controlling pain.

The team also observed less addiction-associated behavior when a low dose of JZL184 was used before administering morphine or oxycodone. “This suggests that endocannabinoids and opioids may not act together in areas of the brain and spinal cord involved in analgesia,” says Dr. Rajadhyaksha, director of the Center for Substance Abuse Research at Lewis Katz School of Medicine at Temple University. “In contrast, their interaction in brain regions is involved in decreasing reward and dependence.”

Potential drugs like JZL184 are being tested in clinical trials as possible treatments for anxiety disorders. Dr. Lee says he is optimistic about the timeline for testing them in combination with opioids for pain management, “and working toward translating these preclinical findings to help patients.”