For the first time, UNC School of Medicine researchers crystalized the structure of LSD attached to a human serotonin receptor of a brain cell, and they may have discovered why an “acid trip” lasts so long.
A tiny tab of acid on the tongue. A daylong trip through hallucinations and assorted other psychedelic experiences For the first time, researchers at the UNC School of Medicine 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.

Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics in the UNC School of Medicine, led the research, which was published in the journal Cell.

“There are different levels of understanding for how drugs like LSD work,” Roth said. “The most fundamental level is to find out how the drug binds to a receptor on a cell. The only way to do that is to solve the structure. And to do that, you need x–ray crystallography, the gold standard.”

That is what Roth’s lab accomplished – essentially “freezing” LSD attached to a receptor so his team could capture crystallography images. As it turns out, 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.

“We think this lid is likely why the effects of LSD can last so long,” said Roth, who holds a joint appointment at the UNC Eshelman School of Pharmacy. “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.”

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.

Postdoctoral researchers Daniel Wacker, PhD, and Sheng Wang, PhD, led the experiments to crystallize LSD bound to a serotonin receptor and discover why it stays bound so long. “Serotonin, obviously, hits this receptor on brain cells,” Wacker said. “But our experiments show that serotonin does not interact with this lid in the same way LSD does.”

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. Roth’s 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.