Then (1943), LSD: My Problem Child
Bicycle Day Chemistry: What Hofmann Synthesized
Hofmann synthesized LSD-25 from lysergic acid, derived from ergot alkaloids, in April 1943. He accidentally absorbed a small amount, experienced mild effects, and then deliberately took an amount he believed was tiny. It was in fact several times larger than what is now understood to be active.
partially-confirmed
A 2017 X-ray crystal structure of LSD bound to the 5-HT2A receptor (Wacker et al., Cell) revealed why the drug lasts so long: a 'lid' from an extracellular loop traps the drug in the receptor for hours. Hofmann's first deliberate dose, chosen because he thought it would be below the active threshold, is now understood to have been several times a typical active dose, explaining the overwhelming intensity he experienced. The structure also explains LSD's extreme potency: its molecular shape allows nearly perfect complementarity with the receptor binding site.
Sources
- Hofmann, LSD: My Problem Child (1979)
- Wacker et al., Cell (2017)
- Preller & Vollenweider, Front Psychiatry (2019)