"Magic mushrooms" are not hallucinogenic but also antidepressant The Chinese research team set out to modify hallucinogens

Hallucinogens, as a psychoactive substance that can cause hallucinations, have attracted much attention in recent years because of their potential therapeutic effects in depression, anxiety, drug addiction, and more. However, the clinical use of hallucinogens in the treatment of depression is still limited.

On January 28, the Chinese research team published a blockbuster article in the journal Science, revealing the molecular mechanism of hallucinogens binding to 5-HT2A receptors and designing new non-hallucinogenic antidepressants, which has aroused heated discussion in the academic community and will promote the progress of new antidepressant therapies and benefit more depressed patients.

The research was conducted by The Research Group of Cheng Jianjun of the iHuman Institute of ShanghaiTech University and the Wang Sheng Research Group of the Center for Excellence in Molecular and Cell Science of the Chinese Academy of Sciences (Institute of Biochemistry and Cell Biology).

Study co-corresponding author Cheng Jianjun said in an interview with the first financial reporter on January 29 that the hallucinogenic effect of hallucinogens is currently known to be achieved by activating the serotonin 5-HT2A receptor, but its precise molecular mechanism of action has not been elucidated.

"The results of this study deeply elucidate the mechanism of action of hallucinogen molecules, provide important ideas for the design of new fast-acting and long-acting antidepressants based on 5-HT2A receptors, and provide important guidance for the design of non-hallucinogenic 5-HT2A receptor agonists." Cheng Jianjun told the first financial reporter.

By analyzing the crystal structure of serotonin (5-HT), psilocybin (also known as "psilocybin"), lygotyldiethylamine (LSD) and the analogue ergoacetamide (Lisuride) and the crystal structure of the 5-HT2A receptor complex, and systematically analyzing the structure of known 5-HT2A receptor antagonists, the research team designed a series of novel 5-HT2A receptor agonists, including the compound IHCH-7086.

"Mouse behavioral studies have shown that the compound does not produce significant hallucinogenic effects in mouse experiments." Cheng Jianjun told the first financial reporter.

The research team further investigated the antidepressant effects of the compound IHCH-7086 and its analogues. Studies have shown that although it does not have a hallucinogenic effect, IHCH-7086 has an antidepressant effect similar to that of hallucinogens such as psilocybine or ergotyldiethylamine, and this effect can be blocked by 5-HT2A receptor antagonists.

In recent years, multiple hallucinogens have shown some potential in the treatment of depression. A natural hallucinogen psilocybin extracted from the "magic mushroom" was awarded by the US FDA in 2019 as a breakthrough therapy for the treatment of major depressive disorder and drug-resistant depression, and the results of the second phase of clinical studies showed that psilocybin can greatly improve the symptoms of depressed patients within one day with a single dose, and the effect can last for more than three months.

But the hallucinogenic side effects of hallucinogens greatly limit their clinical research and widespread application. According to the World Health Organization, there are about 300 million people with depression worldwide. Traditional antidepressants currently on the market often take up to weeks or even months to take effect and have no improvement effect on one-third of patients with refractory depression.

Cheng Jianjun told the first financial reporter: "Due to the large side effects of hallucinogens, so this type of drug was only used for major depression and refractory depression before, and the new drug mechanism we have now discovered has transformed this hallucinogen, which is expected to quickly play an antidepressant effect without hallucinogen." This will greatly expand the use of patients. ”

Cheng Jianjun said that there are currently a large number of research teams engaged in the research and development of antidepressants around the world, but drug research and development takes time. The newly published research has only elucidated the mechanism of drug action at the molecular level, from basic research to clinically usable drugs, and also goes through a long process from the molecular and animal level to human trials.

Cheng Jianjun told the first financial reporter that the team is still further evaluating and optimizing the compound, and he looks forward to the breakthrough in clinical trials of this new type of drug in the next two years.