Antidepressant Psychedelics Could Be Separated From Hallucinations, Suggest Crystal Structure Researchers

Researchers find potentially non-hallucinatory psychedelic compounds by examining crystal structures.

Are hallucinations essential to psychedelic medicine?

Psychedelic drugs are being increasinglyanalyzedfor their potential to benefit patients with psychiatric and neurological conditions. Onelong-recognizedcomplication of taking psychedelic drugs for mental health conditions is the tendency of these compounds to induce hallucinations.

These experiences can be distressing and often last hours, making it harder to design psychedelic interventions that users could take outside a supervised clinical context. The strength of these hallucinations may also potentially dissuade some users from considering psychedelics as a therapeutic option.

Research still knows very little about psychedelic hallucinations. Why do they happen? Why do they differ between compounds? Are they essential to the beneficial effects of psychedelics?

A preclinical study in mice has illuminated some of the confusion around hallucinations by revealing the molecular interactions that psychedelics induce. The findings, published inScienceby a team of Chinese researchers, suggest that molecules that target the same receptor as psychedelics like psilocin (the active ingredient in psilocybin) and LSD can exert antidepressant effects without corresponding hallucinations.

A central receptor

Most psychedelic compounds exert their effects on the brain through one type of receptor, the human serotonin 2A receptor (5-HT_2AR). Using a technique calledX-ray crystallography, the team, led by senior authorSheng Wangof the Chinese Academy of Sciences, were able to capture the exact conformation of the complexes formed by psilocin and LSD when they respectively bind to the 5-HT_2AR.

They then showed that both molecules had a second potential binding position, locking into a narrow cleft in the 5-HT_2AR called the extended binding pocket (EBP). Based on these findings, the team then went to work on creating their own compounds that could bind to 5-HT_2AR by targeting the EBP. These novel structures were customized versions of the 5-HT_2AR-binding antipsychotic lumateperone.

Twitching mice

To test explore how these different modes of binding might affect the function, the researchers dosed mice with LSD and their series of analog compounds. To their surprise, two compounds, the catchily named IHCH-7079 and IHCH-7086, failed to produce a reaction in mice called the head-twitch response.

A solid foundation

Despite their seemingly non-hallucinatory action, the compounds, like LSD, reduced depressive-like behaviors in mice, suggesting the two processes may be separable. “These findings provide a solid foundation for the structure-based design of safe and effective non-hallucinogenic, rapid-acting antidepressants,” said the authors in an email toTechnology Networks.

While these initial findings might eventually make for more flexible and effective psychedelic medicines, the authors were necessarily cautious about their study, which remains at an extremely early stage. “It should be pointed out that the compounds reported in this work are not approved drugs, and further preclinical and clinical studies are needed to verify their safety and antidepressant effects in humans,” concluded the researchers.

Reference: Cao, D, Yu, J, Wang, H, et al. Structure-based discovery of nonhallucinogenic psychedelic analogs.Science. 2022;375(6579):403-411. doi:10.1126/science.abl8615