Why synthetic pot could be the future of pain relief
It’s dangerous. It’s toxic. And it may provide hope for millions in agony.
They call it the holy grail of pain-relief research: a medicine that is comparable to the strongest opioids but lacks their potentially devastating side effects. When biophysicist and structural biologist Kaavya Krishna Kumar set out looking for a novel way to develop one, she knew she needed to start with a substance that hit the body incredibly hard. So she took to the seedier corners of the online forum Reddit, where she learned about an illicit street drug with a reputation for making people both very high and very sick.
“It’s OUT OF THIS WORLD POTENT,” read one recreational user’s post. “A very, very small, almost invisible amount of powder skyrockets you into stoned euphoria.”
The drug is called FUBINACA, and it’s what’s known as a synthetic cannabinoid, a molecule designed in a lab to target the same parts of the nervous system affected by tetrahydrocannabinol, or THC, the main psychoactive compound in cannabis. Underground chemists have been making drugs like it since the early 2000s, when recreational marijuana was still criminalized in the United States and synthetic cannabinoids began catching on as cheap, quasi-legal alternatives. From their powdered form, they’re typically dissolved into solvents, which are then sprayed onto plant shreds to be sold, with a wink, as incense or potpourri. “Not for human consumption,” the label may read—a dodge against regulation.
Sold under monikers like spice or K2, these gray market synthetics have raised public health alarms for both their toxicity and their contamination risks. The exact chemicals and their concentrations can vary from product to product, with side effects ranging from mania to heart attacks.
But Krishna Kumar—then at Stanford Medicine, now at Weill Cornell Medicine—saw in FUBINACA a tool for better understanding how our pain-management system works. And after some clever molecular modeling, she and a team led by researchers from Stanford and Washington University School of Medicine in St. Louis devised an innovative way of modifying it. Earlier this year, the team published a study showing a FUBINACA-derived drug providing sustained pain relief in mice, seemingly without psychoactive or tolerance-building side effects. Such side effects have stymied progress on other would-be cannabinoid pain relievers, dampening enthusiasm for what once seemed like a promising opioid alternative. Now some scientists hope the research can breathe new life into that work—and perhaps open up even wider therapeutic frontiers.
Read more of our reporting in The New Cannabis
Fubinaca wasn’t always a street drug. It was developed by Pfizer and patented in 2009, part of an effort to create “a superpowered aspirin with no side effects,” according to former Pfizer chemist Darin Jones. Like THC, synthetic cannabinoids activate a powerful chemical receptor known as CB1. In humans and other mammals, CB1 is found on nerve cells in the brain and, crucially, on cells elsewhere in the body. It’s known to influence not only the perception of pain but also sleep, metabolism, and memory, making it a promising target for pharmaceutical research. (A second cannabinoid receptor, CB2, seems mostly to regulate the functions of immune cells.)
Of course, the path to market for any new drug must take into account future profitability. And while it’s unclear just what scuttled Pfizer’s research, Jones theorizes it had to do with the increasing legality of medical marijuana, which was suddenly “pennies a pound” at proliferating dispensaries.
But when the company published its patent, that became a blueprint for so-called garage chemists to replicate the formula and create analogues. The U.S. Drug Enforcement Administration reports that law enforcement has encountered hundreds of different synthetic cannabinoids, most of them manufactured in Asia. Variants of Pfizer’s FUBINACA, the first of which was detected in Japan in 2012, are known as some of the most toxic. In 2014 dozens of deaths in Russia were linked to an analogue called MDMB-FUBINACA. Two years later, another variant was behind a mass overdose in Brooklyn, New York, that the media characterized as a “zombie outbreak.”
But Krishna Kumar hoped to pick up where Pfizer left off, harnessing that potency. First, she examined how MDMB-FUBINACA attached to human CB1 receptors in a dish. Compared to other synthetic cannabinoids, she found, it held tighter and activated effects more powerfully.
Then, using a Nobel Prize–winning technology called cryo-electron microscopy (cryo-EM), she flash froze that FUBINACA molecule while it was affixed to CB1 and scanned the conjoined pair with a beam of electrons. The result was a 3D picture, down to individual atoms, of how the drug fit so well into a pocket, or binding site, on the receptor’s surface—like a key in a lock.
That image provided a starting point for designing new versions of FUBINACA that might, by stimulating the receptor in new ways, keep the original’s potency while limiting side effects. For that, Krishna Kumar turned to Susruta Majumdar, a Washington University chemist and pharmacologist, whose lab had previously shown that activating a particular site on an opioid receptor could inhibit chemical reactions that lead to tolerance. Might this be possible for CB1?
The researchers knew that CB1, a cousin to that opioid receptor, had a potential binding site with similar qualities—but it was deep inside the receptor and, in Krishna Kumar’s cryo-EM snapshot, blocked by clusters of atoms. It was also the wrong shape to fit FUBINACA. So Majumdar’s team started sketching bespoke attachments for the cannabinoid, chains of atoms that might help the molecule worm its way in.
Meanwhile, Stanford scientists took another approach, animating the static snapshot using computer simulations, showing how atoms in the drug and the receptor moved around each other. The simulations revealed something surprising: The atom clusters blocking that tantalizing site sporadically moved aside, opening what biochemists call a cryptic pocket, allowing researchers a glimpse in.
Tweaking their designs to fit, Majumdar’s team made one other crucial adjustment in the hope of nixing FUBINACA’s psychoactive side effects. The newly accessible site, it turned out, could accept a compound with a positive electric charge, which hinders a molecule from crossing the membrane separating blood from the brain. By tacking a charged group of atoms onto FUBINACA, researchers confined its activity to CB1 receptors outside the brain—where it can’t get anyone high or act on the brain’s reward circuitry, limiting risks of misuse and abuse.
New versions of FUBINACA were injected into rodents experiencing various kinds of pain. And one variant, which the researchers called VIP36, showed indicators of relieving chronic pain from three different sources—inflammation, nerve damage, and headaches—even after days of repeated injections. True, says Washington University neurobiologist Robert Gereau, all that molecular tinkering had reduced the drug’s potency—and thus its pain-relieving effects. But where that might have left other cannabinoids toothless, Gereau says, VIP36 remained “effective in a range that is useful clinically,” precisely because FUBINACA packed such a wallop to begin with.
VIP36 is still in its baby steps phase. It has yet to be tested in humans, who have fewer CB1 receptors outside of their brains than rodents do. And, for now, the new compound can’t be taken orally, only injected.
But even if the drug never reaches your medicine cabinet, the research could still chart new pharmaceutical paths. For one, it might occasion a reassessment from those skeptical of cannabinoids’ potential as medicine—a constituency that includes the world’s largest pain-research organization, the International Association for the Study of Pain, whose official position is that science has so far failed to prove cannabinoids either safe or effective. “This is the perfect paper to help re-put steam into the cannabinoid field,” says Michael Burton, a neuroscientist and cannabinoid researcher at the University of Texas at Dallas.
What’s more, Majumdar says, there may be other cryptic pockets in other receptors related to CB1, many of which have nothing to do with pain. Some have been linked to heart disease, for instance, or substance abuse disorders. This opens an enticing possibility: What the researchers have learned about changing a receptor’s behavior could help them tinker with a whole range of drugs. Majumdar is already planning to revisit a previous study that unsuccessfully targeted a hard-to-reach opioid receptor. He imagines redesigning antidepressants, maybe cancer drugs. “Targeting diseases beyond pain is expected in the near future,” he says. “We are just scratching the surface.”
Set Design: Mat Cullen, Lalaland Artists
