The 5-hydroxytryptamine receptor 2A (5HTR2A) binds to serotonin (5-hydroxytryptamine) and additional neurotransmitters to modulate changes in perception, mood, and neural activity. Additionally, studies have confirmed that 5HTR2A is one of the primary receptors for psychedelic compounds, such as lysergic acid diethylamide (LSD), and largely mediates the activation of signaling pathways that induce hallucinogenic states. LSD is categorized amongst structurally-similar ergot-derived compounds, ergolines, used to treat a wide variety of illnesses. Several non-hallucinogenic ergolines, such as lisuride, are almost identical in structure to LSD. The structural requirements for inducing hallucinogenic states are not completely understood. Although the downstream cellular signaling effects and molecular structures of 5HTR2A bound to LSD and lisuride have been determined, a comprehensive comparison of the structural changes in 5HTR2A induced by hallucinogenic and non-hallucinogenic ergolines has yet to be performed. Molecular dynamics (MD) simulations have been used to study protein-drug interactions and conformational changes over various timescales. Thus, MD simulations of hallucinogenic (LSD, 1D-LSD, ergine) and non-hallucinogenic (lisuride, methylergometrine, three non-psychoactive isomers of LSD) ergoline derivatives binding to 5HTR2A were conducted. In summary, τ-randomly accelerated MD simulations revealed that hallucinogenic compounds share similar intermolecular dissociation pathways and markedly high affinities and low dissociation rates. Novel conformational pathways were discovered using umbrella sampling MD, which revealed consistent structural changes in 5HTR2A with hallucinogenic compared to non-hallucinogenic compounds. These data may be used to better understand the mechanisms underlying psychedelic-induced hallucinations and predict the hallucinogenic potential of novel non-hallucinogenic psychedelics designed to treat depression, anxiety, and other mental conditions.