Researchers in China have engineered two new chemical compounds that capture the pain-killing benefits of cannabis while avoiding the high risks of addiction and tolerance typically associated with the drug.

The study, published on April 13 in the journal Cell, represents a potential milestone for millions of chronic pain patients who are seeking safer alternatives to opioids.

While cannabis has been used medicinally for thousands of years, from ancient Rome to modern clinics, its use is strictly limited. The primary hurdle has been "dissociating toxicity from efficacy", according to lead researcher Li Xiaoming, a professor and vice-president at Zhejiang University.

In simpler terms, scientists have struggled to keep the medicine while disposing of the "poison" that causes cognitive impairment and dependency.

The breakthrough centers on a specific protein in the brain called cannabinoid receptor 1, or CB1. Scientists view a receptor as a specialized "lock" on the surface of a nerve cell; when a chemical "key" such as cannabis fits into this lock, it sends a signal to the brain.

Li's team discovered that the CB1 receptor operates like a fork in the road, sending signals down two different paths. One path mediates therapeutic effects like pain relief, while the other triggers side effects such as addiction and drug tolerance.

Standard cannabis-based drugs are essentially clumsy keys that unlock both paths simultaneously. To solve this, the team used artificial intelligence models to design "biased" compounds.

These are precision-engineered molecules designed to fit the lock in a way that only triggers the pain-relief pathway. Li described the process as a form of chemical surgery performed with molecular precision.

In laboratory tests, the two novel compounds proved effective at treating both inflammatory pain, which is caused by injury or swelling, and neuropathic pain, which is chronic pain caused by nerve damage. Crucially, the animals involved in the study showed no signs of addictive behavior and no decrease in the drug's effectiveness over time. The researchers also observed fewer impacts on physical movement and body temperature compared to traditional treatments.

The research builds on the team's 2023 discovery, when they first deciphered the structure of CB1 bound to a side-effect-related signaling protein. By understanding the exact signaling mechanism of the side effect pathway, they were able to build molecules that avoid it entirely.

The team is currently refining the compounds and conducting further safety validations in preparation for clinical trials. Li said the ultimate goal is to move from basic research to developing drugs that can genuinely improve the quality of life for patients.

chenye@chinadaily.com.cn