LSD's lid action found to be reason for long-lasting trips

A little goes a long way ... that's the idea behind microdosing, the Silicon Valley productivity trend that involves taking tiny amounts – about a tenth of a full dose – of LSD to boost focus and creativity. Before you dismiss this as some new age hipster nonsense, a new study revealing the reason acid trips last such a long time suggests that its proponents might not be that far out of their minds.

For all its notoriety as the "It" drug of the 1960s counterculture movement, little is known about LSD, not least the reason behind its potency and effect on the brain. It's certainly not for want of trying, though. To understand how a drug like LSD works, scientists first need to figure out how it binds itself to a receptor on a cell, explains lead author Bryan Roth, a professor of pharmacology at the University of North Carolina (UNC).

"The only way to do that is to solve the structure," he says. "And to do that, you need x-ray crystallography (a technique used to determine the atomic and molecular structure of a material by shining x-rays at it), the gold standard."

All this sounds simple enough, but the road to this discovery is one littered with failure. In fact, it took Roth and his lab 20 years of trial and error before they found a way to crystallize LSD molecules attached to a receptor. It's a crucial first step that has thwarted many scientists because without crystals, it's impossible to see what LSD bound to a receptor looks like.

The Roth lab finally succeeded by "freezing" LSD attached to the protein 5-HT2B, a receptor for the neurotransmitter serotonin, which regulates mood balance. Not only did this enable the scientists to capture a psychedelic drug in action for the first time, it also led to a surprising and important discovery: how part of the serotonin receptor folds over and locks the LSD molecule into place when it latches on, which possibly explains why the effects of LSD can last up to an entire day, depending on the size of the hit.

"We think this lid is likely why the effects of LSD can last so long," says Roth. "LSD takes a long time to get onto the receptor, and then once it's on, it doesn't come off. And the reason is this lid."

This finding also debunks suggestions that LSD "washes" out of the brain's fluid within four hours. According to pharmacology postdoctoral fellow and study co-author John McCorvy speaking to Live Science, once it latches on to the receptor, it doesn't budge for the next eight to 12 hours.

That said, the researchers also found that this lid is unique to LSD bound to serotonin receptors; when they tested mutant receptors with floppier lids on the molecules, they discovered that while the drug attached itself more quickly, it also detached from the receptor just as easily. In addition, shorter binding times also led to different signalling patterns inside cells, which suggest that these effects would differ from those produced by an LSD-serotonin structure.

LSD as psychotherapy

Can LSD be used as medical therapy? Albert Hoffmann, the Swiss chemist who discovered the effects of the drug in 1943, an event that has since been commemorated as Bicycle Day, certainly thought so. In fact, though he acknowledged its dangers and lamented the way it was used as a recreational drug in the 60s, he also considered it "medicine for the soul," which, when properly used, could jumpstart the "inborn faculty of visionary experience" that we possess as children but lose on our journey into adulthood.

In recent years, other researchers have also stepped up to defend the drug, with recent studies showing its potential to alleviate anxiety and depression. Now that the structure of the drug bound to a receptor has been revealed, there's a chance this finding could help drug developers design better psychiatric drugs with fewer side effects. And while the study doesn't address the issue of microdosing, Roth says that it does offer insight into how the drug can have an effect even in tiny doses.

"The fact that LSD gets trapped provides an explanation for why extremely small amounts of the drug can still be potent," he tells Nature. "Before this, what I heard from Silicon Valley was purely anecdotal."

That said, whatever its therapeutic effects, people should exercise caution with it. "We do not advocate using LSD; it is potentially very dangerous," he says. "But it could have potential medicinal uses, some of which were reported in the medical literature decades ago. Now that we've solved the structure of LSD bound to a receptor, we are learning what makes it so potent."

The study has been published in the journal Cell.

Source: UNC Healthcare