Science (New York, N.Y.)Jan 27, 2022

Finding non-hallucinogenic psychedelic-like compounds using their structure

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 3, 2026

Abstract

Structures of the serotonin 2A receptor complexed with psilocin and LSD reveal a second binding mode.

Psilocin and serotonin have an additional binding mode alongside the primary one.
This second binding mode facilitated the design of the psychedelic IHCH-7113.
IHCH-7113 is a substructure of the antipsychotic lumateperone.
Several 5-HTR β-arrestin-biased agonists exhibiting antidepressant-like activity were identified in mice.
These agonists demonstrated effects without hallucinogenic properties.

Simplified

Drugs that target the human serotonin 2A receptor (5-HTR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HTR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HTR β-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HTR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects. 2A2A2A2A

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Finding non-hallucinogenic psychedelic-like compounds using their structure

Abstract

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