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

The recent resurgence of classical psychedelic compounds, specifically 5-HT_2A receptor agonists, as potential therapeutics has led to numerous initiatives aimed at better understanding the mechanisms underlying their effects. Psychedelic compounds are commonly known as hallucinogens. One of the major outstanding questions in the field is whether altered states of consciousness-the hallucinogenic or psychedelic experience-is a prerequisite for the therapeutic effect. As a result, several academic and commercial efforts are focused on developing 5-HT_2A receptor agonists that are speculated not to have these consciousness-altering effects. However, these efforts largely rely on chemical analogs of supposedly non-hallucinogenic 5-HT_2A receptor agonists, such as lisuride and ergotamine. Our review of the literature indicates that there is no basis for claiming that lisuride or ergotamine are non-hallucinogenic at relevant concentrations in the brain. This does not invalidate current efforts to produce non-hallucinogenic 5-HT_2A receptor agonists for the potential benefit of patients, but it calls for caution in the reliance on animal data in the pursuit of such compounds and highlights the need for rigorous determination of target engagement in humans before claiming that 5-HT_2A receptor agonists are non-hallucinogenic.