According to the World Health Organization, approximately 280 million people worldwide live with depression. About two-thirds of those with depression have suicidal ideation, and 25% attempt suicide. Suicide is also one of the leading causes of death in 15–29-year-olds, with nearly 50% of suicides occurring in people with depression. However, conventional antidepressants produce effects only after weeks of daily dosing and do not alleviate all disease symptoms. Furthermore, 30% of patients with depression don’t respond to current antidepressant therapy.
In a study published in the journal Science, the labs led by Dr. WANG Sheng at the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, and Dr Cheng Jianjun at the iHuman Institute, ShanghaiTech University reported for the first time a structure-based strategy to design novel rapid-acting antidepressant compounds, a discovery that could accelerate the discovery of non-hallucinogenic psychedelic analogues.
Over the past ten years, many researchers and clinicians have come to believe that psychedelic pharmacology may represent a new era in psychiatric therapeutics. Most clinical studies described during this time have focused on psilocybin, a compound found in the Psilocybe genus of mushrooms, some of which were used for healing and spiritual purposes by the Mayan and Aztec cultures of Mesoamerica.
The US Food and Drug Administration granted psilocybin ‘breakthrough therapy’ status for the treatment of major depressive disorder and drug-resistant depression in 2019. The results of a phase II clinical trial showed that psilocybin can greatly improve the symptoms of patients with depression within one day after dosing, and the effect can last for more than three months. However, the hallucinogenic effects of these drugs remain a concern, and scientists have been unsure whether hallucinations are therapeutically important or just a side effect.
Psilocybin is converted in the liver to pharmacologically active psilocin, which then acts on serotonin 2A receptors (5-HT2AR) in the brain. In this study, scientists produced six new crystal structures of 5-HT2AR that bound to compounds including psilocin, lysergic acid diethylamide (i.e., LSD, one of the most potent psychedelics), serotonin, and non-hallucinogenic psychedelic analogues. They found that psilocin displayed an unexpected binding mode known as the extended binding pocket (EBP) mode, which is regulated by lipids. They also found that compounds that occupied more EBP than orthosteric binding pocket (OBP, the usual site for receptor binding) were associated with anti-depressive activity in test animals without triggering hallucinations. Thus, scientists designed several new psychedelic analogues they thought would favor EBP binding over OBP binding.
Scientists then repeated the behavioral tests on mice receiving these compounds and found that two compounds, dubbed IHCH-7079 and IHCH-7806, did not trigger head twitch behavior, which has long been seen as indicative of hallucinations. However, the mice displayed standard behavioral measures suggesting the compounds were effective antidepressants.
These findings provide a solid foundation for the structure-based design of safe and effective non-hallucinogenic, rapid-acting antidepressants. 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.