Painkiller mimics cannabis without the psychoactive side effects

A molecule that targets the same receptor as the active ingredient in cannabis could lead scientists to new drugs for chronic pain. Chemists designed the compound, known as VIP36, to bind cannabinoid receptor 1 (CB1) in the body but not in the brain. This design prevents the molecule from having psychoactive side effects. In mouse studies, VIP36 treated inflammatory pain, nerve pain, and migraines (Nature 2025, DOI: 10.1038/s41586-025-08618-7).

Scientists searching for nonopioid pain relievers have long sought compounds that target CB1. But these molecules typically get shuttled to CB1 in the brain instead of to CB1 in the body’s sensory neurons. Many CB1-targeting molecules are also associated with tolerance—needing to take more and more of a compound to achieve the same painkilling effect.

“We were trying to understand if you could separate analgesia through peripheral receptors from these other issues of psychoactivity and tolerance,” says Robert W. Gereau IV, a researcher at Washington University in St. Louis (WUSTL) who led the development of VIP36 along with WUSTL colleague Susruta Majumdar and Stanford University’s Kaavya Krishna Kumar and Ron O. Dror.

VIP36’s structure combines the potent CB1 agonist MDMB-Fubinaca with a tail that has a guanidinium group, which is positively charged in the body. That charge prevents it from crossing the blood-brain barrier.

Computational studies also revealed a hidden binding pocket in CB1. “We found an aspartate deep in the binding pocket, and that aspartate could form a salt bridge interaction with the guanidinium group,” Majumdar says. That interaction appears to mediate signaling that’s associated with tolerance.

Because VIP36 must be injected, the researchers plan next to tweak the molecule so it can be taken orally.

In a commentary that appears with the study, the University of Aberdeen’s Iain R. Greig and the University of Toronto’s Ruth A. Ross write, “Pain conditions in humans are highly complex and many cannabinoid receptor agonists that show promise in rodents are not successful in human trials. . . . Nevertheless, we anticipate that other research groups will soon try to modify other cannabinoids in a similar way, and we eagerly look forward to the results.”