LSD is one of the most potent hallucinogenic drugs—active at just around 100 micrograms…a miniscule amount. That fact has fascinated pharmacologists for decades. Namely, how can it have such long-lasting effects…12 hours or more…at such tiny doses? 

To find out, researchers legally obtained LSD. And built copies of the receptors it binds to in the brain—serotonin receptors. They mixed the LSD and the receptors together, and crystallized the result. They then imaged the structure, using x-ray crystallography.

And they found that when LSD linked up with the serotonin receptor, a sort of "lid" formed over it. Almost like the drug went in, then pulled the door shut behind it. "You could think of the top part of LSD as a hand, holding onto the latch and pulling it down." Bryan Roth, a pharmacologist at University of North Carolina in Chapel Hill involved in the research. 

"This explains why LSD is so potent, why such a small amount of it is active, and secondly why it lasts for such a long period of time. Because basically once it gets in there it takes hours to come off the receptor." The study is in the journal Cell. [Daniel Wacker et al., Crystal Structure of an LSD-Bound Human Serotonin Receptor]

The result may also explain why microdosing—taking even smaller amounts of LSD, at sub-psychedelic levels—might work as a mood enhancer, as some users have reported. "It's clear from the data we have that these small doses can engage these receptors, and of course we know that the receptors that LSD interacts with, they're the same receptors that are thought to be involved in antidepressant drug action." 

Roth does not advocate trying it out. But he says the discovery of the "lid" might someday lead to the development of novel antidepressants—ones with long-lasting effects, at just the tiniest of doses.

—Christopher Intagliata

[The above text is a transcript of this podcast.]