Summary- Significant progress was made on this project, which involves the preclinical development of candidate medications for stimulant use disorders. Three relevant papers were published in peer-reviewed journals over the last year. One article describes the pharmacology of potential agonist medications acting at monoamine transporters, whereas two other articles report the pharmacology of psychedelic medications acting as agonists at 5-HT2A receptors. Emerging evidence suggests that psychedelic-assisted therapy could be useful for treating substance use disorders, including cocaine use disorder, but the underlying mechanisms involved are poorly understood. In particular, it is unclear whether acute subjective effects of psychedelic drugs are required for their long-term efficacy in treating various psychiatric disorders. In a key original research publication, our team characterized the biological effects of the psychedelic drug, lysergic acid diethylamide (LSD), as compared to its non-psychedelic analog, lisuride. We were especially interested in elucidating the properties of lisuride that contribute its lack of psychedelic activity. Both LSD and lisuride are known to activate 5-HT2A receptors in the brain, but lisuride also acts as a potent agonist at the serotonin 1A (5-HT1A) receptor, a property known to counteract psychedelic effects. For our study, we hypothesized that lisuride lacks psychedelic activity due to a dual mechanism: 1] partial agonism at 5-HT2A receptors and 2] full agonism at 5-HT1A receptors. The in vitro effects of lisuride, LSD, and related analogs on 5-HT2A signaling were characterized using miniGαq and ß-arrestin 2 recruitment assays. The 5-HT1A- and 5-HT2A-mediated effects of lisuride and LSD were also compared in male C57BL/6J mice. The in vitro results confirmed that LSD is an agonist at 5-HT2A receptors, with high efficacy and potency for recruiting miniGαq and ß-arrestin 2. By contrast, lisuride displayed partial efficacy for both functional endpoints (6 - 52% of LSD or 5-HT Emax), and antagonized the effects of LSD. The mouse experiments demonstrated that LSD induces head twitch responses (HTRs)(ED50=0.039 mg/kg), while lisuride suppresses HTRs. Lisuride also produced potent hypothermia and hypolocomotion (ED50=0.008-0.023 mg/kg) that was blocked by the 5-HT1A antagonist WAY100635 (3 mg/kg). Blockade of 5-HT1A receptors prior to lisuride restored basal HTRs, but failed to increase HTRs above baseline levels. HTRs induced by LSD were blocked by lisuride (0.03 mg/kg) or the 5-HT1A agonist 8-OH-DPAT (1 mg/kg). Our findings show that lisuride is an ultra-potent 5-HT1A receptor agonist in C57BL/6J mice, limiting its use as a 5-HT2A ligand in mouse studies. Results also indicate that the 5-HT2A partial agonist/antagonist activity of lisuride explains its lack of psychedelic effects. Thus, lisuride displays a unique pharmacology which combines potent full-efficacy agonism at 5-HT1A receptors with weak partial-efficacy agonism at 5-HT2A receptors. This profile of receptor activity might be leveraged to create safe and efficacious "non-psychedelic" LSD analogs for treating various psychiatric conditions, including stimulant use disorder.