Innovative Method Showed How Psychedelics Bind to Serotonin Receptor: Study
Wed, April 21, 2021

Innovative Method Showed How Psychedelics Bind to Serotonin Receptor: Study

 

A new study unveiled how psychedelic drugs bind a key cell receptor in the brain. The identification of the binding process could lead to newer drugs for anxiety, depression, and substance use.

The binding of psychedelic drugs to a brain cell receptor was revealed by scientists at the University of North Carolina (UNC) Health Care, not-for-profit healthcare in the US. Their research could exploit the capability of psychedelic drugs to treat serious psychiatric conditions. By discovering the binding process, methods could be developed to mitigate the common serious side effect of these drugs. They published their findings in the journal Cell.

What Are Psychedelics?

Several naturally occurring or synthetically made substances alter certain functions of the brain. These substances can change someone's cognitive function, mood, and perception. These substances are called psychedelics, according to the Australian organization Alcohol and Drug Foundation. A person who is exposed to a psychedelic may hear or see things, may feel different emotions, and may strangely perceive time. As such, many psychedelics can induce hallucinations.

 

 

Statista, a German portal for statistics, showed that many US high school students were exposed to hallucinogenic drugs, such as angel dust and mushroom, in 2017. In a survey from September 2016 to September 2017, a total of 14,956 high school respondents expressed their use of particular hallucinogenic substances. Across all ethnicities and genders, 6.6% of respondents used a hallucinogenic drug.

Between genders, 7.6% of male and 5.5% of female high school students used a type of hallucinogenic substance in 2017. Among races, 7.2% of non-Hispanic Whites, 3.3% of non-Hispanic Blacks, and 7.1% of Hispanics used hallucinogenic drugs. Among races between males, 7.9% of non-Hispanic Whites, 4.8% of non-Hispanic Blacks, and 8.2% of Hispanics used hallucinogenic drugs. And among races between females, 6.4% of non-Hispanic Whites, 1.4% of non-Hispanic Blacks, and 5.8% of Hispanics used hallucinogenic drugs.

In the UK, a different survey from January 1 to December 31, 2018, of 13,338 children aged 11 to 15 years showed the proportion of those exposed to psychedelics. Among aged 15 years, 5.6% of boys and 4.8% of girls have taken psychedelics. Among aged 14 years, 3% of boys and 2.7% of girls have taken psychedelics. Among aged 13 years, 1.7% of boys and 1% of girls have taken psychedelics. Among aged 12 years, 0.9% of boys and 0.1% of girls have taken psychedelics. And finally, among aged 11 years, 0.1% of boys and girls have taken psychedelics.

First Detailed Structure of Psychedelics Bound to Serotonin Receptor

Normally, psychiatrists will not use psychedelics for most patients with serious psychiatric disorders. This is despite the therapeutic advantages of the drugs. The main reason is the severe side effects, primarily hallucinations, which may be experienced by patients. Also, hallucinations may not help patients who are already experiencing the same thing due to their condition. But if these adverse mental effects can be greatly reduced, psychedelics are promising therapies for many patients worldwide.

At UNC Health Care, a team of scientists discovered the cell receptor in the brain targeted by psychedelic drugs, including LSD, psilocybin, and mescaline. These drugs have been recognized for both pros and cons. The pros are the significant potential in treating major depressive disorder and other serious mental health conditions. The cons are severe and usually long-lasting hallucinations that can be detrimental to patients. But the discovery in the interactions of those drugs shed some light on the biological and molecular dynamics inside the brain.

 

 

"Gaining this first glimpse of how they act at the molecular level is really important, a key to understanding how they work. Given the remarkable efficacy of psilocybin for depression (in Phase II trials), we are confident our findings will accelerate the discovery of fast-acting antidepressants and potentially new drugs to treat other conditions, such as severe anxiety and substance use disorder," said Dr. Bryan L. Roth, a study's senior author and professor of pharmacology at the UNC School of Medicine.

In the study, the team collaborated with Georgio Skiniotis at Stanford. They solved the high-resolution structure of the mentioned psychedelic drugs. They solved it by actively binding the substances to the 5-HT2A serotonin receptor or HTR2A, located on the brain cells. The structure would allow them to study and alter the chemical composition of the drugs. But to bind the receptor, they needed a robust method to highlight the interactions.

The study's co-first author Kuglae Kim investigated different experimental methods to purify and stabilize HTR2A. And among numerous methods, crystallization was the most optimal in maintaining the quality of the serotonin receptors. As such, Kim's solution yielded the first x-ray crystallography structure of the brain receptors. The structure showed LSD bound to the receptor. While the application of cryo-EM featured 25-CN-NBOH, a prototypical hallucinogen, bound to the whole receptor complex. This complex could control the release of neurotransmitters in the brain, which influence several neurological and biological processes.

The structure is similar to a map of the whole serotonin receptor interacting with psychedelic drugs. Because scientists can see the details, they can assess what functions are influenced by bound psychedelics. At the same time, it can show them what the receptor does upon exposure to different psychedelics. Experts believe that when receptors are exposed to psychedelics, receptors cause neurons to fire signals in an asynchronous and disorganized manner. This chaotic signaling is like a noise in the brain. Fortunately, the map reveals the specifics of the noise.

Scientists are now moving forward using that structure. They are now exploring precise compounds capable of removing hallucinations from psychedelics. However, the removal of hallucinatory effects must not eliminate the therapeutic benefits. If possible, they will alter the chemical composition of existing psychedelic drugs to increase the therapeutic potential and decrease the risk of hallucinations.

The discovery of the interactions between psychedelics and serotonin receptors is crucial in therapies involving those drugs. Even though the FDA has approved certain psychedelics like mushrooms, there is still a lot of room for improvement, specifically in the safety profile. If hallucinations can be removed without reducing effectiveness, it will result in a scientific breakthrough.