Then (1979), LSD: My Problem Child
LSD's Crystal Structure and the Duration Mechanism
Hofmann knew that LSD was extraordinarily potent, active in extremely small amounts, and lasted 8-12 hours, far longer than the blood concentration alone could explain. He attributed the duration to LSD's tight receptor binding without knowing the specific mechanism. He described the experience as 'self-reinforcing', once it begins, it continues regardless of what the body does with the drug chemically.
confirmed
Wacker et al. (Cell, 2017) solved the crystal structure of LSD bound to the 5-HT2A serotonin receptor at atomic resolution. The structure revealed a 'lid' mechanism: after LSD binds to the receptor, an extracellular loop (EL2) closes over the binding site like a trap door, locking LSD inside the receptor for hours. The receptor remains activated long after LSD has been metabolized and cleared from the bloodstream. This kinetic trap explains both the duration and the impossibility of rapidly reversing LSD effects with an antagonist, the antagonist cannot displace the trapped LSD. Hofmann's intuition that the duration was receptor-based was correct; the specific mechanism was unknown until 74 years after his first synthesis.