The prototypical hallucinogen LSD acts via serotonin receptors， and here we describe the crystal structure?of LSD in complex with the human serotonin receptor 5-HT. The complex reveals conformational rearrangements to accommodate LSD， providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HTR and 5-HTR-a major target for its psychoactivity. 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. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics， stereochemistry， and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP.