Structure of LSD attached to a brain cell serotonin receptor revealed!

Structure of LSD attached to a brain cell serotonin receptor revealed!

A tiny tab of acid on the tongue. A daylong trip through hallucinations and assorted other psychedelic experiences For the first time, researchers have discovered precisely what the drug lysergic acid diethylamide (LSD) looks like in its active state when attached to a human serotonin receptor of a brain cell, and their first-ever crystal structure revealed a major clue for why the psychoactive effects of LSD last so long and the work was published in Cell.

When LSD latches onto a brain cell's serotonin receptor, the LSD molecule is locked into place because part of the receptor folds over the drug molecule, like a lid. And then it stays put.

Eventually, though, an acid trip ends. Some LSD molecules pop off their receptors as the lid moves around. Also, brain cells eventually respond to this strange molecule by sucking the receptor into the cell, where it - along with the LSD -- is degraded or disassembled for recycling.

Although other labs have reported that LSD "washes" out of the brain's fluid within four hours, such experiments could not determine what was happening on or inside brain cells. The lab has shown for the first time that LSD is very much not washed out of the serotonin receptors located within the membrane of brain cells in a few hours.

Solving the structure of LSD could help drug developers design better psychiatric drugs with fewer side effects. Also, although LSD is illegal, it remains a popular recreational drug and not just for its most potent effects. Some people - most notably technology developers in Silicon Valley and elsewhere - report "microdosing" LSD to boost creativity, relieve stress, and help them solve problems, while avoiding its hallucinogenic effects.

One in 10 people in the United States -- tens of millions of people -- have reported using LSD at least once in their lives. "About 3 percent of all high school students -- who are at an age when their brains are still developing -- have reported trying it," senior author said. "And although the drug has been used for a long time, we don't know that much about it."

They created mutant receptors with floppier lids, and found that LSD bound more quickly and also detached from the receptor more easily. They also noticed that the shorter binding times led to different signaling patterns inside cells. These different patterns likely means that the effects of LSD would have been different than the typical effects with the lid tightly secured.

Computer simulations were done to confirm that this is what might happen when LSD engages its receptor protein in a human brain.