For decades, the mainstream remedy against chronic pain has been waged with a double-edged sword: opioids. These powerful drugs are efficient at dulling pain, but they also hijack the brain’s reward system, leading to addiction and, too often, death. In 2022 alone, opioids were linked to 82,000 overdose deaths in the U.S.

Aware of the risks, many have turned to cannabis, which has some pain-numbing effects. But it comes with the drawback of intoxication and the risk of addiction if used heavily. Some patients aren’t exactly fond of the psychoactive effects of cannabis use, but they see it as an acceptable substitute for dangerous opioid medication.

Now, scientists have taken a significant step toward a safer alternative — a compound inspired by cannabis that relieves pain without the addictive or mind-altering side effects.

Researchers at Washington University School of Medicine in St. Louis and Stanford University designed a synthetic molecule that mimics the pain-relieving properties of cannabinoids — natural compounds found in the cannabis plant—but with an important caveat: it can’t reach the brain.

“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,” said Susruta Majumdar, PhD, a professor of anesthesiology at Washington University Medicine and the study’s senior author.

“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.”

A Cannabis-like Medicine Without the High

Cannabis has been used for thousands of years to treat pain, but its psychoactive effects are a drawback. Cannabinoid molecules bind to a receptor called CB1 on brain cells. This interaction triggers the “high” associated with marijuana. But CB1 receptors are also found on pain-sensing nerve cells throughout the body. So the researchers wondered whether they could target these nerve cells for pain relief — and thereby avoid the brain altogether.

The researchers achieved this by designing a cannabinoid molecule with a positive charge, which prevents it from crossing the blood-brain barrier. “We were able to overcome that issue,” said Robert W. Gereau, PhD, co-corresponding author and director of the Washington University Medicine Pain Center. The modified molecule binds only to CB1 receptors outside the brain, dulling pain without altering mood or cognition.

The molecule was designed with the help of advanced computational modeling, which uncovered a hidden pocket on the CB1 receptor that had previously been thought to be inaccessible. By targeting this pocket, they found a way to bind CB1 receptors outside the brain while reducing the likelihood of the body developing tolerance to the drug.

They tested the compound on mice that suffered from nerve-injury pain and migraines. The pain made the mice hypersensitive to touch. After the compound was injected, the mice weren’t jittery anymore when they were gently touched. Even after twice-daily treatments over nine days, the mice showed no signs of needing higher doses to achieve the same level of pain relief. In other words, this medicine didn’t seem to build tolerance, just as designed.

What Comes Next?

“Designing molecules that relieve pain with minimal side effects is challenging to accomplish,” said Majumdar. But this discovery opens the door to a new class of painkillers that could offer long-term relief without the risks of addiction or overdose.

The researchers next plan to develop the compound into an oral drug for clinical trials. If successful, it could provide hope for the estimated 50 million Americans living with chronic pain.

For now, the research remains in its early stages. Hopefully, clinical trials may start soon at some point.

The findings appeared in the journal Nature.