LSD may latch on to brain cells for hours: study

Lysergic acid diethylamide - more commonly known as 'LSD' or 'acid' - gets trapped into the receptor cells in the brain for hours, say scientists who have explained why the drug is one of the longest lasting and most potent hallucinogens.
Scientists captured images of an LSD molecule bound to a human serotonin receptor and discovered that the LSD molecule was wedged into the receptor's binding pocket at an angle no one had expected.
On top of that, part of the receptor protein had folded in over the LSD like a lid, sealing the drug inside.
"Once LSD gets in the receptor, a lid comes over the LSD, so it's basically trapped in the receptor and can't get out," said Bryan Roth, a professor at University of North Carolina in the US.

"LSD takes a really long time to get on the receptor, and then once it gets on, it doesn't get off," he said.
The finding explains why LSD trips last for a full day, even though LSD doses are extremely small - the average dose is 100 or so microgrammes - and LSD molecules are cleared from the bloodstream in a couple of hours.

Given that there has been a tentative resurgence in testing LSD for some medical conditions, understanding the mechanism of its potent and long-lasting actions may help drug developers design more effective psychiatric drugs with fewer side effects, researchers said.

While speculative, the study may help researchers think about how LSD micro-dosing could work.
People are increasingly taking LSD at doses too small to cause hallucinations with the goal of boosting their creativity and countering depression, researchers said.
LSD micro-dosing has never been clinically tested, and many scientists have doubted that taking such small amounts of the drug would have any detectable effect.
However, when Roth's group exposed live cells in a petri dish to micro-dose-sized amounts of LSD, those tiny doses of LSD affected the receptors' signalling.
It is as yet unknown how this signalling would translate into an effect on a person's mood or perception, although the studies demonstrate LSD's remarkably potent actions on cellular signalling.

LSD's ability to fit in and let the receptor's "lid" close over it depends on the specific chemical structures of both the drug and the receptor.
When the team exposed cells with mutant receptors that had floppier lids to LSD, the LSD bound more quickly and also exited the receptor much faster.
Those short LSD binding events produced very different signaling patterns than the longer binding events.
"I think it's important for the pharmaceutical industry to understand that even if you modify just one tiny aspect of any compound, you may affect the way the entire compound sits in the receptor, and that affects the compound's performance," said Daniel Wacker, a postdoctoral fellow at UNC.

The study was published in the journal Cell.