LSD Lasts So Long Because It Burrows Into Your Serotonin Receptors

By
Illustration: Daniel Wacker

Hallucinogens are having a bit of a moment right now: Clinical studies suggest that they have remarkable therapeutic effects, including helping people quit smoking or reduce anxiety, thanks to their tendency to dissolve your ego, integrate your brain systems, and help you gain a new perspective on life.

Among these drugs, LSD — short for lysergic acid diethylamide — is known for its absurdly long trips, lasting 10, 12, 15 hours or more, on a teensy standard dose of 100 micrograms. In a just-released paper in Cell, a research team led by University of North Carolina postdoc Daniel Wacker finds that it’s the exceptional chemical structure of LSD that accounts for those long-lasting, super-potent hallucinogenic journeys.

The team used crystallography images, which show how a molecule is arranged, to look at how LSD binds to the receptors for serotonin, a neurotransmitter that carries signals along nerves and is related to mood stabilization. The team produced powerful x-rays by using a high-end particle accelerator, the Advanced Photon Source. The process is epic: “What we do is to expose the LSD-bound receptor, which we have forced to form a crystal, to the x-rays,” Wacker explained to Science of Us over email. “Where there are atoms the x-rays get diffracted, where there are none the x-rays pass straight through. This way we can reconstruct a 3-D image of where the atoms are and look at the exact interactions between LSD and the receptor.”

That imaging revealed something exceptional about LSD: Most receptors in the brain have “lids,” he says, or little extracellular loops at the entrance of the area where binding happens. But lids tend to be loose — compounds go in and come out at they please. LSD holds onto the “latch” of the receptor, and because it does so, the lid doesn’t move anymore, and the mischievous compound is sealed in, as in a bunker, as shown in the illustration Wacker shared with us. Serotonin acts on the same receptor but isn’t nearly as insistent on hanging around.

Illustration: Daniel Wacker

This also explains the compound’s slow “off rate”: It’s super sticky, and even if it’s cleared from your blood and even your spinal fluid, it’s still tucked into your brain, sprinkling hallucinations into your visual field. This may have further clinical applications, Wacker says: If other drugs could be developed to seal themselves in the same way, their potency and duration could go up, too. This also shows how studying traditionally recreational drugs can have effects across medicine, he says.

LSD Lasts So Long Because It Seals Itself in Your Receptors