View attachment 53943 Research is first to demonstrate precisely how the compound lysergic acid diethylamide attaches to serotonin receptors in the brain
“You can hear the Universal Symphony with God singing solo and Holy Ghost on drums,” was how Hunter S. Thompson described the experience, while the Beatles famously sang about “tangerine trees and marmalade skies”.
Scientists are still some way from understanding how LSD brings about altered states of consciousness, but they have finally identified why acid trips last so long.
A new study is the first to demonstrate precisely how the compound lysergic acid diethylamide (LSD) attaches to serotonin receptors in the brain.
The images reveal that once the LSD compound latches on, part of the serotonin receptor folds down over it like a dustbin lid, meaning that it is held tightly in place allowing the drug to linger in the brain for up to 12 hours.
Bryan Roth, a professor of pharmacology at University of North Carolina and a senior co-author on the study said: “It’s basically trapped in the receptor and can’t get out.”
Roth’s interest in the subject was sparked after witnessing the effects of LSD on fellow music fans at Grateful Dead concerts in his youth.
“It would be interesting to be in the parking lot hearing people wondering when their LSD experience was going to end,” says “A lot of people who take the drug are not aware of just how long it lasts.”
However, it has taken two decades of painstaking trial and error to manage to transform the LSD and receptor into a crystallised form. This allowed the scientists to decipher its exact physical structure, using crystallography, a technique where x-rays are beamed into a material and the resultant diffraction pattern can be used to work out the exact spacing of the atoms.
The study, published in Cell, also found that eventually brain cells respond to the attached molecule by sucking the receptor inwards, like a tortoise pulling its head into its shell, at which point the LSD is broken down.
In future, the findings could help chemists produce shorter-acting versions of the drug that may be more suited to clinical use for anxiety or post traumatic stress disorder.
Thursday 26 January 2017 12.33 EST
Hannah Devlin Science correspondent
Images: Fredrik Skold/Alamy, Wacker et al
Crystal Structure of an LSD-Bound Human Serotonin Receptor
Daniel Wacker, Sheng Wang, John D. McCorvy, Robin M. Betz, A.J. Venkatakrishnan, Anat Levit, Katherine Lansu, Zachary L. Schools, Tao Che, David E. Nichol, Brian K. Shoichet, Ron O. , Bryan L. Roth
- Crystal structure of the human 5-HT2B receptor bound to LSD is determined
- LSD shows unexpected binding configuration in the orthosteric site
- LSD has extremely slow on and off rate at 5-HT2B and 5-HT2A receptors
- Accelerated LSD kinetics selectively reduce arrestin signaling at 5-HT2B and 5-HT2Az
The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD’s key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR—a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD’s slow binding kinetics may be due to a “lid” formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD’s binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors.
Full article here: http://www.cell.com/cell/fulltext/S0092-8674(16)31749-4