Researchers build rapid-acting antidepressant compounds that are non-hallucinogenic

The World Health Organization estimates that nearly 280 million people worldwide suffer from depression. Suicidal ideation affects roughly two-thirds of those suffering from depression, and 25% attempt suicide.

Suicide is also one of the top causes of mortality in people aged 15 to 29, with nearly half of all suicides occurring in people suffering from depression. Conventional antidepressants, on the other hand, cause reactions only after weeks of daily medications and do not relieve symptoms completely. Furthermore, existing antidepressant therapy does not work for 30% of patients with depression.

In a study published in the journal Science, the researchers reported for the first time, a structure-based strategy to design novel rapid-acting antidepressant compounds—a discovery that could accelerate the invention of non-hallucinogenic psychedelic analogs.

The research was conducted in laboratories led by Dr Sheng Wang at the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, and Dr Jianjun Cheng at the iHuman Institute, ShanghaiTech University.

Several clinicians and researchers have begun to believe that psychedelic pharmacology may herald a revolutionary change in psychiatric therapeutics over the last ten years. The majority of clinical studies reported during this time period have concentrated on psilocybin, a compound found in the Psilocybe genus of mushrooms, many of which were used for curing and religious purposes by Mesoamerica’s Mayan and Aztec cultures.

In 2019, the US Food and Drug Administration designated psilocybin as a “breakthrough therapy” for the treatment of major depressive disorder and drug-resistant depression. A phase II clinical trial found that psilocybin can greatly work on the clinical signs of depressed patients within one day of medication, and the effect can last for more than three months.

However, the hallucinogenic effects of these drugs continue to be a source of concern, with researchers uncertain whether hallucinations are therapeutically essential or simply a side effect.

Psilocybin is modified in the liver to the pharmacologically active psilocin, which then functions on the brain’s serotonin 2A receptors (5-HT2AR). Researchers created six new crystal structures of 5-HT2AR that bound to compounds such as psilocin, lysergic acid diethylamide (i.e., LSD, one of the most potent psychedelics), serotonin, and non-hallucinogenic psychedelic analogs in this analysis.

Researchers discovered that psilocin has an unusual binding mode called as extended binding pocket (EBP), which is controlled by lipids. They also observed that compounds that conquered more EBP than orthosteric binding pocket (i.e., OBP, the common site for receptor binding) had anti-depressive activity in test animals without causing hallucinations.

As a result, scientists created a number of new psychedelic analogs that they believed would favor EBP binding over OBP binding.

Researchers then repeated the behavioral tests on mice given these compounds and discovered that two compounds, dubbed IHCH-7079 and IHCH-7806, did not cause head twitch behavior, which has long been associated with hallucinations. The mice, on the other hand, demonstrated standard behavioral measures, indicating that the compounds were beneficial antidepressants.

These observations act as a base for the structure-based layout of non-hallucinogenic, rapid-acting antidepressants that are both safe and reliable. It should be noted that the compounds described in this study are not approved drugs, and more preclinical and clinical research is required to confirm their stability and antidepressant effects on the human body.

Source:
Journal reference:

Cao, D., et al, (2022) Structure-based discovery of nonhallucinogenic psychedelic analogs. Science. doi/10.1126/science.abl8615.

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