Many may not know that depression is on the rise and is the leading cause of disability throughout the world. If cases of depression are increasing, so are cases of suicide. The need for effective treatment is not only important for restoring one’s health but also for returning functioning and quality of life.
Current antidepressants can have some serious side effects, as most pharmaceuticals do. Fortunately, Chinese scientists have developed non-hallucinogenic antidepressant compounds. Could this be the beginning of a life-changing solution for millions across the globe?
A press release announcing the scientists’ research explains that the team has “designed two new compounds that can relieve depression but do not cause the unwanted effect of hallucination.” Why is it important to understand that this potential solution for depression does not include hallucinations? Because the antidepressant compounds are derived from psychedelics, a class of substances that trigger non-ordinary states of consciousness.
The scientists are from the Center for Excellence in Molecular Cell Science, which falls under the Chinese Academy of Sciences and ShanghaiTech University. The researchers mapped out the crystal structure of psilocybin, a serotonergic psychedelic associated with hallucinations that is also receiving increased attention for its therapeutic potential. This psychedelic is a strong agonist of serotonin 2A receptors and is hypothesized to benefit us as a result of its ability to stimulate serotonergic neurotransmission.
In their report, the scientists explain that “drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases”—and we know that psilocybin in magic mushrooms does target that serotonin receptor. However, the biggest problem with psychedelics such as psilocybin is the fact that they produce hallucinogenic effects, which can sometimes lead to paranoia or uncomfortable sensitivity to texture, sight, sound, etc.
To be precise, when consumers eat magic mushrooms, or “shrooms,” the psilocybin is converted into psilocin through the liver, which then acts on the 5-HT2AR in the brain. This means that it is able to cross the blood-brain barrier as well as share the same tryptamine structure as serotonin, which allows its “affinity for certain central nervous system serotonin receptors.”
Once the researchers mapped out the crystal structure of psilocybin when it was bonded to the serotonin 2A receptors, they found a previously unknown binding place—which was found to be linked with the antidepressant pathway that does not cause hallucinations. This new binding place is regulated by lipids and serotonin and is apparently a binding place for psilocybin and its receptors.
Without the discovery of this new binding place, the researchers would not have been able to develop the non-hallucinogenic antidepressant compounds. With the molecular pathway of this binding place, the researchers were able to develop two new compounds that mainly act on the new binding place.
The team made use of mice to conduct a mouse model test, in which high doses of the compounds did not induce head twitch behavior—an indicator of hallucinations in the test subjects. The scientists also found that the compounds maintained similar antidepressant effects as with psychedelics but with the added benefit of no hallucinations. The mice also displayed reductions in freezing behavior, which is indicative of antidepressant effectivity.
Dr. Wang Sheng, the lead in the study, explained that the findings provide us with a foundation for the structural design of safe and effective non-hallucinogenic rapid-acting antidepressants. The researchers explain that the new binding site, or mode, is in addition to the already known canonical mode. This discovery could “accelerate the discovery of non-hallucinogenic psychedelic analogs,” meaning more people could benefit from the therapeutic properties of psychedelics.
This is significantly important, as more than 30% of depression patients currently do not respond to their antidepressant therapy. In 2019, the U.S. Food and Drug Administration (FDA) gave psilocybin the “breakthrough therapy” status so that it may be used for treatment in major depressive disorder and drug-resistant depression.
In 2017, Sheng was a co-author for a study on the crystal structure of an LSD-bound human serotonin receptor. In that study, the team found that LSD “occupied a pocket within 5-HT2AR [the 2A serotonin receptor] called the orthosteric binding pocket (OBP).” During this new round of research, they found that psilocybin occupied, or rather touched, a “neighboring site called the extended binding pocket (EBP) in a process mediated by lipids,” which would be the aforementioned new binding place.
Fierce Biotech explains that EBP and OBP are both linked to antidepressant activity without hallucinations. Understanding that EBP is linked like that, the researchers were able to design the compounds in such a way that they not only act rapidly but also favor the EBP binding site. The two non-hallucinogenic but rapid and effective antidepressant compounds are “dubbed IHCH-7086 and IHCH-7079.”
Now that we know there is a means of consuming psychedelic-like compounds for their benefits without hallucinations, how can one be sure of its medical efficacy? Well, there is already plenty of evidence suggesting that psilocybin is so effective for depression that even the treatment-resistant forms can’t escape it. While there are quite a few places where one can get psychedelic therapy in a legal, safe and professional-facilitated environment, the substances are still largely illegal and it is not recommended that one self-medicates.
At the moment, these new compounds that could improve the lives of many are yet to be made into medication that is ready to hit the shelves of pharmacies. This brilliant team of Chinese scientists is currently working on perfecting the drug’s design so that it may one day become a candidate for human testing.
Considering the increasing prevalence of depression and what comes along with it, we hope that the team and its novel compounds progress effectively but quickly and that when the time comes, the authorities in charge will allow human trials since there is no risk of hallucinations.
While the findings from this research are very exciting and show significant promise for those with depression, Sheng stated 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.”
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