Summary: Wired reports on a new scientific paper published in Cell Press explaining the neuroscience behind LSD’s lasting effect on the brain. Wired speaks to MAPS Founder Rick Doblin, Ph.D., about how this new study affects research into the therapeutic effects of LSD. “While this new paper is fascinating from a neurobiological perspective, it doesn’t contribute any useful information to how to enhance the efficacy or the safety of LSD-assisted psychotherapy,” explains Doblin. “This isn’t to say that mechanism of action research isn’t important and valuable, it’s just to say that I don’t see any way that the new information about LSD’s mechanism of action will translate to enhancing therapeutic methods or increasing safety.”
Originally appearing here.
Few tropes in modern America are as enduring as the LSD Trip Gone Far Too Long. It should all be over after a few hours, right? OK maybe not. Eight? Ten? Probably should have cleared more of my calendar.
Even though science has long had an intimate relationship with LSD—chemist Albert Hofmann first synthesized it way back in the ‘30s—why the drug insists on producing such lengthy hallucinations hasn’t been so clear. Until now. A new paper out today in Cell finally reveals the secret of the LSD Trip Gone Far Too Long: The drug binds to receptors in your brain in a fascinating way, essentially locking into position to guarantee a good, long burn. And that could have big implications for harnessing LSD as a therapeutic drug.
Now, your body will clear LSD from your bloodstream in a matter of hours. But not your brain. Specifically, not the serotonin receptors that LSD binds to in the claustrum region of the brain. “Once LSD gets in the receptor, you can think of it as a hole in the ground. LSD jumps into it and then pulls a lid down over the top,” says study co-author Bryan Roth, a pharmacologist at the University of North Carolina at Chapel Hill School of Medicine. “Basically, from the structure we could tell that once LSD gets in there it can’t get out. That’s why it lasts so long.” We’re talking 12, 18, maybe 24 hours, by the way. Still, that lid will move around, so some LSD molecules will escape as the high wears off.
It turns out catching an LSD molecule and its receptor in action is a staggeringly difficult thing to do. First, Roth and his colleagues needed receptors—but you can’t just pluck them out of someone’s brain. So instead, study co-author Daniel Wacker, also of UNC, engineered them (the receptors, not the people). He began by mixing up a harmless virus and insect cells. “The virus infects these cells, hijacks their machinery, and basically produces those receptors for us,” Wacker says. “And then we go in and crack open those cells and take out those receptors.”
The receptors, though, are very flexible and wily: Some bend this way, others that way. So to image them, the team had to freeze the receptors in time with crystallization. “A crystal by definition is the same exact molecule, the same exact configuration over and over and over again as a three dimensional arrangement,” says Wacker. It’s the same principle as salt crystals forming as a bowl of soup evaporates—only on a much, much smaller scale.
Now, with the X-rays you get at the dentist, only 10 percent of the rays will actually hit an atom to produce an image. The same would go for trying to image crystallized receptors. So the researchers used the Argonne National Laboratory’s Advanced Photon Source to fire a concentrated beam of x-rays at the crystals. “Now if you shoot a lot more at them, you will get a lot more data out of it,” says Wacker, “because it’ll always be 10 percent.”
What Roth and his colleagues are finding is that the longer the receptor and LSD are in proximity, the better the LSD gets at activating the receptor. Meaning, a very small dose could still have an effect. That could have implications for so-called microdosing, in which users ingest a tiny amount of LSD, supposedly to treat things like depression and increase productivity. “Our results actually suggest that microdosing probably is having some effect,” says Roth. “It doesn’t say that the effect is beneficial or not, but it does give a biological and a chemical and a structural explanation for how these vanishingly small doses of LSD can actually have effects.”
Now’s as good a time as any to remind readers that while LSD shows medical promise, it’s still very much illegal in the United States. And even if people could use it legally, those interested in it as a therapeutic might not want those pesky trips. “We can begin to determine whether the psychedelic experience is part and parcel of all the potential therapeutic effects,” Roth says. “It may or may not be, but the structure basically gives us the potential to design drugs that may have the beneficial actions without the deleterious effects.”
But hold up, says Rick Doblin, founder of the Multidisciplinary Association for Psychedelic Studies. If the FDA were to approve LSD, it’d need evidence of safety and efficacy, not mechanism of action. “While this new paper is fascinating from a neurobiological perspective,” he says, “it doesn’t contribute any useful information to how to enhance the efficacy or the safety of LSD-assisted psychotherapy.”
“This isn’t to say that mechanism of action research isn’t important and valuable,” he adds, “it’s just to say that I don’t see any way that the new information about LSD’s mechanism of action will translate to enhancing therapeutic methods or increasing safety.”
But hey, science is progress. This study certainly didn’t take the understanding of LSD backwards. Teasing apart its structure is a step toward controlling the drug. “We can actually present alternative routes—how to make derivatives of LSD, slight modifications to it—so we can create tool compounds that then are actually allowed by the FDA to study things,” says Wacker.
So who knows, maybe one day your doctor will prescribe a derivative of LSD—without the LSD Trip Gone Far Too Long, of course.