“Structure-Based Discovery of Non-Hallucinogenic Psychedelic Analogs”, 2022-01-28 (; similar):
Non-hallucinogenic psychedelic analogs: Psychedelic drugs such as lysergic acid diethylamide (LSD) and mushroom-derived psilocybin exert their effects by binding the serotonin 2A receptor (5-HT2AR). These drugs also have antidepressant effects, but the hallucinations they cause complicate their use as therapeutics. et al 2022 present structures of 5-HT2AR bound to psychedelic drugs, the endogenous ligand serotonin, and the non-hallucinogenic drug lisuride. The structures reveal ligand-receptor interactions that cause a bias toward arrestin recruitment. Based on these insights, the authors designed arrestin-biased ligands that displayed antidepressant-like activity in mice without hallucination effects. Arrestin recruitment alone is insufficient for antidepressant effects, but the low G-protein signaling of the arrestin-biased ligands appears to allow antidepressant effects without causing hallucination.
Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use.
Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) & D-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the non-hallucinogenic 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-HT2AR β-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects.
The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective non-hallucinogenic psychedelic analogs with therapeutic effects.
…Additionally, although 2 recent studies have reported non-hallucinogenic psychedelic analogs with antidepressant-like behavior (15, 16), it remains unclear how to rationally design such compounds…and it is unclear whether the hallucinogenic effects of psychedelics are necessary for therapeutic effects (2, 7, 8, 9, 10).
[Like the research on dissociating ketamine’s psychedelic effects from its anti-depressant effects, work on “trip-free psychedelics” raise the question of how much of the therapeutic benefit comes from the trip and how much from low-level neurological changes. If the latter, and they can be separated, then the weird beliefs & personality changes of heavy-using psychedelicists may be unnecessary: perhaps those simply reflect the enhanced neuroplasticity during the trip while weird experiences happen to extreme disruption of normal cognition like object recognition or concept of self, and are irrelevant to the benefits (rather than themselves producing the benefits as most psychedelicists strongly believe).]