Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists?

The article critically examines whether lisuride and ergotamine, both 5-hydroxytryptamine (serotonin) 2A receptor (5-HT2AR) agonists, can be considered non-hallucinogenic, a claim often cited in scientific literature. It finds that ergotamine's low brain penetration likely explains its lack of psychedelic effects rather than a unique receptor interaction, while lisuride, structurally similar to LSD, can induce hallucinations at higher doses that achieve sufficient 5-HT2AR occupancy, particularly in Parkinson's disease patients. The review emphasizes that claims of non-hallucinogenic 5-HT2AR agonists require rigorous human pharmacokinetic and psychometric evidence to confirm relevant brain receptor engagement. Although lisuride and ergotamine do not support the notion of non-hallucinogenic 5-HT2AR agonists, ongoing research into other compounds may yield therapeutics with reduced or altered psychedelic effects.