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

A review of the literature on 5-HT2A receptor agonists, including psychedelics like LSD and the supposedly non-hallucinogenic compounds lisuride and ergotamine, finds no evidence that lisuride or ergotamine are non-hallucinogenic at relevant brain concentrations. This challenges the assumption that altered states of consciousness are not a prerequisite for therapeutic effects. The authors caution against relying solely on animal data when developing non-hallucinogenic 5-HT2A receptor agonists and emphasize the need for rigorous human studies to confirm target engagement before claiming a compound is non-hallucinogenic.

Study at a glance

Abstract

The recent resurgence of classical psychedelic compounds, specifically 5-HT2A 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-HT2A 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-HT2A 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-HT2A 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-HT2A receptor agonists are non-hallucinogenic.