March 5 (UPI) — Researchers say they have reproduced the pain-relieving effects of cannabis with a synthesized compound that avoids the mind-altering, addictive qualities of the natural plant.
Their study was published Wednesday in the journal Nature.
The researchers at Washington University School of Medicine in St. Louis and Stanford University say their experiments on mice have shown that the modified cannabinoid compound, which uses specially tailored molecules, binds to pain-sensing nerve cells in the body much like natural cannabis and delivers similar pain relief.
But in a key difference, the synthetic molecules carry a positive charge that prevents them from crossing the blood-brain barrier into the brain, eliminating the mind-altering side effects that make cannabis addictive.
Moreover, the researchers found evidence that repeated use of the compound does not produce a tolerance like opioid pain relievers do, in which ever-higher doses are needed to achieve the same effects.
The study, funded by the National Institutes of Health, comes as scientists are on a quest to develop a safe, effective alternative to opioids, whose addictive qualities have caused more than 2.5 million American adults to develop opioid use disorders.
Some 81,000 overdose deaths involving opioids occurred in 2023, despite widespread public health warnings and media attention.
Knowing the dangers of opioids, chronic pain sufferers have turned to marijuana for centuries as a safer alternative. And it’s an effective one: according to wide-ranging 2017 scientific review by the National Academies of Sciences, Engineering and Medicine, conclusive or substantial evidence exists that cannabis or cannabinoids are effective for treating chronic pain in adults.
Even so, its psychoactive side effects have remained problematic, preventing cannabis from being considered as a viable alternative to opioids for pain relief.
“However, we were able to overcome that issue,” the new study’s authors state.
Washington University School of Medicine researcher Susruta Majumdar, a professor in the school’s anesthesiology department, said the compound, known as “VIP36,” works by binding to the cannabinoid “CB1” receptors on nerve cells found in the body’s central and peripheral nervous systems, much as natural cannabinoids do, and reduce pain signals.
But the compound differs from cannabis in a key respect.
“We observed that VIP36 is functionally selective, and in-vivo, [it] stays in the periphery and does not penetrate the brain,” Majumdar told UPI in an email.
“This compound is analgesic in multiple pain models, such as inflammatory pain, neuropathic and migraine pain, all without side effects at therapeutic dose,” he said.
“This drug has significant implications for chronic pain treatment via peripheral CB1 activation but also could revolutionize the design of drugs targeting other [pain receptors].”
The other exciting element of the research led by Majumdar and Washington University School of Medicine colleague Robert Gereau is their discovery through sophisticated computer modeling that the CB1 receptor has a hidden “pocket” that is unavailable for natural cannabis and opioids, but can be opened and tapped by VIP36 to minimize the build-up of tolerance to analgesics.
With 10% of the U.S. population suffering from chronic pain, the implications of an effective, non-addictive synthetic cannabinoid compound could be considerable, Majumdar said, adding that he and his colleagues are now aiming to perfect the compound so it can be delivered in a pill or a transdermal patch as they prepare for a future clinical trial — a process that could take up to eight years with funding from private sources and the NIH.
“It has been the goal of the past decade since we all become more aware of the opioid crisis that everyone is trying to find non-opioid molecules that have strong analgesic effects without the habit-forming behavior,” said Dr. Samer Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
Narouze, a past president of the American Society of Regional Anesthesia, told UPI the development of any such non-opioid medications or molecules are “welcome to the field” and noted that the Food and Drug Administration earlier this year approved suzetrigine, sold under the brand name Journavx, as a non-opioid treatment for moderate to severe acute pain in adults.
Journavx’s main ingredient works by targeting a pain-signaling pathway that involves sodium channels in the peripheral nervous system before pain signals reach the brain.
Interest in cannabis, meanwhile, has been more muted because “people are afraid of creating parallel addiction crisis,” Narouze said — perhaps not as bad as opioids, but still enough to dampen its potential as a pain treatment.
He said a synthetic cannabinoid molecule that avoids binding to the high-producing CB1 nerve cell receptors in the brain, but adheres to those in the body’s periphery — say, in the area of a soft tissue injury — would be a positive development in the quest to find substitutes for opioids, although, he added, that quality might limit the compound’s effectiveness to localized pain relief.
