Lucy in the Sky with Diamonds - Why acid trips last so long

Ever wondered why there have been so many urban myths and songs dedicated to LSD? 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. Put simply, the findings, published in ‘Cell’, have now showed that once the LSD compound catches, part of the serotonin receptor folds down over it, meaning that it is held tightly in place and thus allows the drug to perch in the brain for several hours, even up to 12 hours at times.

‘It’s basically trapped in the receptor and can’t get out’. This is how Bryan Roth, senior co-author of the study and professor of pharmacology at the University of North Carolina described his observations.

The potent psychedelic drug LSD, which alters our cognition and perception, gained huge popularity throughout the world during the hippie or counterculture years in the 1960s and 70s as a permitted recreational drug. The drug was however quickly classified as a schedule I drug. Controlled substance schedule I drugs carry with them a high potential for abuse and severe psychological and/or physical dependency, explaining why the drug is categorised in the highest of groups based on the risk of abuse or harm.

In 1968, the possession of LSD was made illegal in the United States, although legally approved and regulated psychiatric use of LSD continued until 1993 in Switzerland. Ever since, scientists have been keen to study its complex pharmacology and more importantly its potential utility in studying aspects of human psychopathology and consciousness.

Two decades of gruelling trial and error later, scientists have finally managed to transform the LSD and receptor into a crystallised form to be able to decipher its exact physical structure. In 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, researchers found that brain cells eventually respond to the attached molecule by sucking the receptor inwards at which point the LSD is broken down.

‘A lot of people who take the drug are not aware of just how long it lasts’, said Roth who’s interest in the topic came following close and personal youthful encounters with party revellers at the infamous Grateful Dead concerts. Grateful Dead concerts were inextricably linked to LSD in the United States and provided the primary distribution network for LSD through the mid-1990s.

In the future, while molecular and crystal studies cannot fully explain the central nervous system (CNS), such studies provide informative insights into hallucinogen actions. Chemists could for example produce shorter-acting versions of the drug that may be more suited to clinical use for anxiety or post-traumatic stress disorders.