Drug analogues like psilocybin and LSD show antidepressant-like activity in mice without causing hallucinations, the researchers report. The results may provide a basis for the structure-based design of safe and effective non-hallucinogenic psychedelic therapeutic drugs.
Serotonin is a neurotransmitter that modulates most human behavioral processes. Drugs that target serotonin receptors, specifically the human serotonin 2A receptor (5-HT2aR), are widely used to treat neuropsychiatric diseases. However, many of these drugs are known to have hallucinogenic effects. Previous research has shown that serotonergic hallucinogens – psychedelics like LSD and psilocybin, which bind to 5-HT2aR – have promising potential as a rapid and long-lasting therapeutic for the treatment of PTSD, anxiety and depression.
Despite this, the characteristic hallucinations caused by these compounds may interfere with their use. According to the authors, non-hallucinogenic psychedelic analogs could offer an alternative solution, but it remains unclear how to rationally design such compounds and whether the hallucinogenic effects of psychedelics are necessary for therapeutic effects. Here, Dongmei Cao and coworkers describe several crystal structures of 5-HT2aR linked to the psychedelic drugs LSD and psilocin, endogenous serotonin and a non-hallucinogenic psychedelic lisuride. They reveal a second binding mode for serotonin and psilocin.
With this new information, Cao et al. used a structure-based approach to design the new psychedelic IHCH-7113 as well as several 5-HTs2aBiased β-arrestin R agonists that showed antidepressant-like activity in mice without hallucinogenic effects. “[W]We anticipate that the structures reported here will accelerate the search for novel psychedelics and non-hallucinogenic psychedelic analogues for the treatment of neuropsychiatric diseases,” the authors write.
American Association for the Advancement of Science (AAAS)
Cao, D. et al. (2022) Structure-based discovery of non-hallucinogenic psychedelic analogues. Science. doi.org/10.1126/science.abl8615.