Differential in Vitro Activation Profiles for Psychedelic versus Non-psychedelic Ergolines at the 5-HT2A Receptor

Serotonergic psychedelics induce their characteristic subjective effects via activation of the serotonin 2A receptor (5-HT2AR). This structurally diverse class of drugs includes ergolines (e.g., LSD), phenethylamines (e.g., mescaline), and tryptamines (e.g., psilocin), all of which have NPS analogues that have emerged on recreational drug markets. Importantly, certain ergolines with structural similarity to LSD, such as lisuride, are unable to evoke psychedelic effects, and the underpinnings of such observations are debated and inconclusive. A selection of psychedelic and non-psychedelic LSD analogs (including lisuride, AL-LAD, and LAMPA) was tested in two in vitro cell-based 5-HT2AR activation assays. These assays monitor the recruitment of β-arrestin 2 (βarr2) or miniGαq, allowing the assessment of potencies and efficacies in both assays, and affording estimates of biased agonism. The known psychedelic compound AL-LAD activated 5-HT2AR in both assays with higher intrinsic efficacies (137 - 167 %) than LSD. Conversely, LAMPA, a compound with poorly defined psychedelic properties, showed slightly decreased potencies and intrinsic efficacies (87 - 89%) compared to LSD in both assays. The non-psychedelic lisuride, displayed a notably decreased efficacy (49%) in the βarr2 assay, and no perceptible recruitment of miniGαq. Collectively, our results suggest that ergoline compounds may need to reach a defined threshold of 5-HT2AR activation, in both βarr2 and miniGαq pathways, to elicit psychedelic subjective effects. This intriguing hypothesis warrants further investigation.