Cannabis has been studied for decades for its pain-relieving potential, but its psychoactive properties have limited its medical use.

Millions of individuals suffer from chronic pain, and for many years, the main treatment has been opioids.

Effective as they are, opioids come with serious risks – they are extremely addictive and can be deadly if abused. The demand for safer pain medication has never been more urgent.

In the search for alternatives that can bring pain relief without the risk of addiction, researchers have discovered a potential solution.

Experts at Washington University School of Medicine in St. Louis and Stanford University have created a new compound that replicates a natural molecule that occurs in cannabis.

This achievement leverages the pain-relieving properties of cannabis without inducing mind-altering side effects. The compound has been tested in mice with some positive results.

The study highlights the potential of this new compound as a non-addictive pain reliever.

Unlike opioids, which act on the brain’s reward system and lead to addiction, this compound was designed to target pain-reducing receptors in the body while preventing entry into the brain.

Dr. Susruta Majumdar is a professor of anesthesiology at WashU Medicine and the study’s senior author.

“There is an urgent need to develop non-addictive treatments for chronic pain, and that’s been a major focus of my lab for the past 15 years,” said Dr. Majumdar.

“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.”

Despite warnings about the dangers of opioid use, overdose deaths remain alarmingly high. In 2022 alone, opioids were linked to approximately 82,000 deaths in the United States. The crisis continues, pushing researchers to find safer alternatives.

Study co-author Dr. Robert W. Gereau is a professor of anesthesiology and director of the WashU Medicine Pain Center. He noted that people have turned to marijuana as a pain treatment for thousands of years.

“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,” said Dr. Gereau.

Cannabinoid molecules in cannabis interact with CB1 receptors on brain cells and pain-sensing nerve cells. These interactions contribute to marijuana’s pain-relieving effects but also cause mind-altering side effects.

Working with Stanford University researchers, the experts modified a cannabinoid molecule by adding a positive charge. This prevents the compound from crossing the blood-brain barrier while still allowing it to bind to CB1 receptors in the body.

By limiting its action to pain-sensing nerve cells outside the brain, they achieved pain relief without the unwanted side effects.

The researchers tested the compound in mouse models of nerve-injury pain and migraine headaches. They measured touch sensitivity as an indicator of pain and found that the modified compound eliminated hypersensitivity in the mice.

The results suggest that the compound could be a powerful pain reliever without the risks associated with opioids.

One major issue with opioid treatments is that patients develop tolerance over time, requiring higher doses for the same effect. This new compound, however, provided prolonged pain relief without signs of tolerance, even with twice-daily treatments over nine days.

The researchers discovered why tolerance was avoided. By using advanced computational modeling, they identified a previously hidden pocket on the CB1 receptor.

This pocket, confirmed through structural models, allows the compound to bind in a way that reduces cellular activity linked to tolerance.

Unlike conventional cannabinoid binding sites, which become less effective over time, the hidden pocket opens briefly, allowing the compound to work without losing its effect.

Designing molecules that relieve pain without unwanted side effects is a complex challenge. Researchers now aim to develop this compound into an oral medication for further testing and, eventually, clinical trials.

If successful, this could mark a significant shift in how chronic pain is treated – offering a safer, non-addictive alternative to opioids.

Millions of people struggle with chronic pain daily. With ongoing research, a new solution could be on the horizon – one that provides relief without the devastating consequences of addiction.

The full study was published in the journal Nature.

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