A New Synthetic Cannabinoid Could Pack A Painkilling Punch – Without The High

Chronic pain is a common problem. A 2023 study from the National Institutes of Health indicated that new cases of chronic pain conditions occur more often in US adults than other prevalent conditions like diabetes and depression. 

While both the understanding and treatment of pain have improved, there’s still a heavy reliance on opioids, despite what we know about their highly addictive nature and potential for harm. As such, scientists are searching for alternatives – and a team from Washington University (WashU) School of Medicine and Stanford University think they may have hit on a new one. 

The compound they’ve designed is based on pain-relieving molecules found in the cannabis plant.

“For millennia, people have turned to [cannabis] as a treatment for pain,” said co-corresponding author and director of the WashU Pain Medicine Center Robert W. Gereau in a statement. “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.”

The way they did it was to design a custom, synthetic cannabinoid molecule that is positively charged, which prevents it from being able to cross the blood-brain barrier. This means it can’t bind to its target – cannabinoid receptor 1 (CB1) – in the brain, but can act on cells in the rest of the body. 

“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,” explained the study’s senior author and professor of anesthesiology at WashU Medicine Susruta Majumdar. 

So far, the compound – called VIP36 – has only been tested in mice, but the results are encouraging. In mouse models of inflammatory, nerve, and migraine pain, VIP36 had a painkilling effect. In the nerve pain model, this effect persisted throughout the nine days of treatment (18 injections total), which the authors say is important as previous efforts with other compounds have elicited tolerance. For chronic pain patients, it’s vital to find a treatment that works for them over the long term. 

What sets VIP36 apart is that it can bind to a “hidden” site on the CB1 receptor that was previously thought to be inaccessible to cannabinoids. The site is nestled inside a pocket that only opens for brief windows of time, and binding here is associated with fewer of the cellular processes that lead to tolerance. Thanks to the computer modeling performed by the Stanford team, the researchers were able to figure this out and use it to their advantage.

With only animal studies so far completed, we’re still in the early stages of the development of this compound. However, the authors hope their research will continue to progress, and are planning the development of an oral drug that will hopefully make it to human clinical trials. 

“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 Majumdar.

The study is published in the journal Nature with an accompanying News and Views article.