Novel Cannabinoid Offers Pain Relief Without Addiction Risk

The search for safer alternatives to opioids for pain relief is more urgent than ever. In a collaboration between Washington University School of Medicine in St. Louis and Stanford University, researchers have developed a cannabinoid compound that provides pain relief without the addictive or psychoactive side effects of cannabis.

The study is published in Nature.

The opioid crisis and the search for safer pain relief

Chronic pain affects millions worldwide, leading many to rely on prescription opioids for relief. While effective in managing acute pain, opioids carry significant risks when used long-term, including addiction and overdose. In 2019, ~600,000 deaths globally were attributed to drug use, with opioids involved in nearly 80% of these cases. This statistic underscores the urgent need for safer, non-addictive pain management alternatives.

For centuries, cannabis has been utilized for its pain-relieving properties. The plant naturally contains numerous compounds known as cannabinoids; this includes tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is primarily responsible for the psychoactive effects associated with marijuana use, such as euphoria and altered sensory perception. CBD, on the other hand, is non-psychoactive and has been studied for its potential therapeutic benefits.

"For millennia, people have turned to marijuana as a treatment for pain. Clinical trials have also 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," said co-corresponding author Dr. Robert W. Gereau, the Dr. Seymour and Rose T. Brown Professor of Anesthesiology and director of the WashU Medicine Pain Center at Washington University School of Medicine in St. Louis.

"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 co-corresponding author Dr. Susruta Majumdar, a professor in the Department of Anesthesiology at Washington University School of Medicine

Designing a non-psychoactive cannabinoid

Gereau and Majumdar engineered a novel cannabinoid compound designed to provide effective pain relief without the psychoactive effects typically associated with cannabis. They focused on creating a modified cannabinoid that selectively targets peripheral pain receptors located outside the brain and spinal cord.

The researchers also used sophisticated computational modeling to identify a previously unknown “cryptic pocket” on the CB1 receptor, a key protein involved in the body’s response to cannabinoids. The CB1 receptor is part of the endocannabinoid system, which plays a crucial role in pain, mood and memory.

Typically, when a cannabinoid interacts with this receptor, it activates the central nervous system, leading to psychoactive effects. The cryptic pocket is not usually exposed under normal conditions. It opens only briefly, and only when the receptor undergoes certain structural changes.  

By identifying this hidden, or “cryptic,” pocket on the receptor, the team realized they could design a compound that would bind to this pocket selectively, triggering pain relief without triggering the brain’s reward system. This method prevents the compound from crossing the blood-brain barrier.

“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,” said Majumdar.

The team also discovered that by binding to this cryptic pocket, the compound was able to reduce the development of tolerance, a common problem with many pain treatments.

The team tested the compound in mouse models of nerve injury and migraine headaches. They measured the mice’s sensitivity to touch, a common indicator of pain perception in animal studies. The compound that showed the most promise, known as VIP36, demonstrated efficacy in three different mouse pain models.

The mice also did not develop tolerance to the compound over a nine-day treatment period, suggesting a potential for sustained efficacy without the need for escalating doses.

Implications and next steps

The development of this new cannabinoid-based pain treatment represents an advancement over previous attempts to use cannabis-derived compounds for pain relief.  By targeting cannabinoid receptors outside the central nervous system, the researchers have eliminated the risk of euphoria, cognitive impairment and addiction – major drawbacks of conventional cannabis-based treatments.

The design principles used in this study could also have implications beyond pain relief. By targeting the cryptic pocket in the CB1 receptor, the research opens up new possibilities for designing drugs that target other G-protein-coupled receptors (GPCRs), potentially changing the way we approach drug development for a variety of conditions.

Despite these promising findings, there are still several hurdles to overcome before this compound can become a viable clinical treatment. Further research is needed to confirm its safety and effectiveness in humans as well as the long-term effects of this compound, including any potential for side effects or unintended interactions with other medications.

Gereau and Majumdar plan to develop the compound into an oral drug that could be evaluated in clinical trials.

Reference: Rangari VA, O’Brien ES, Powers AS, et al. A cryptic pocket in CB1 drives peripheral and functional selectivity. Nature. 2025. doi: 10.1038/s41586-025-08618-7

This article is a rework of a press release issued by Washington University School of Medicine in St. Louis. Material has been edited for length and content.