Does genetics determine your reaction to psychedelics?  A recent study suggests that they could

Does genetics determine your reaction to psychedelics? A recent study suggests that they could

Research on psychedelics like LSD and psilocybin as treatments for substance use disorders, depression, anxiety, and PTSD holds incredible promise. The evidence is so compelling that some states are decriminalizing possession of these drugs and legalizing their therapeutic use, even though they remain under the federal government’s Schedule 1 classification.

New drugs for mental health and substance use disorders are desperately needed. An estimated 30% of people with major depressive disorder do not respond to traditional antidepressants. In March of this year, the CDC recorded the 12-month period with the highest number of drug-related deaths in US history.

As promising as they are, researchers are still unraveling the mechanisms by which they work. In particular, they found that people seem to react differently to various psychedelics. Understanding why this could help researchers identify the optimal psychedelic treatment for a given person.

In July, researchers from the University of North Carolina Chapel Hill published a study in the journal ACS Chemistry Neurosciences this can help us better understand why some people have a therapeutic response to certain psychedelics and others do not. The work could not only serve as a foundation for better understanding these differences, but also help answer outstanding questions about the neurobiology of psychedelics.

Background- Psychedelic drugs like LSD, psilocybin, DMT, and mescaline are called serotonergic psychedelics. These belong to a family of organic compounds called tryptamines and are similar in structure to serotonin, which at least partially explains their affinity for serotonin receptors. Although the exact mechanism of action is not fully understood, we do know that when these compounds bind to a serotonin receptor subtype called the 5-HT2a receptor, it triggers a cascade of actions responsible for changes in cognition, emotion and perception characteristic of psychedelic “trips”.

Research on psychedelics like LSD and psilocybin as treatments for substance use disorders, depression, anxiety, and PTSD is incredibly promising.Getty

However, simple binding to this receptor is not “sufficient to mediate effects on the receptor,” said Bryan Roth, head of the National Institute of Health’s Psychotropic Drug Screening Program and one of the authors. of the study. Reverse. “The receptor must also interact with these proteins called G proteins.”

The 5-HT2A receptor belongs to a family of receptors called G protein-coupled receptors (GPCRs); G protein-coupled receptors (GPCRs) are the largest family of proteins encoded in the human genome. G proteins respond to various stimuli outside of a cell and then activate signaling pathways, which result in activity within a cell.

As in the rest of our body, there are genetic variations of these 5-HT2A receptors. Previous research has identified seven common genetic variations of the 5-HT2A receptor DNA sequence. These variations – called single nucleotide polymorphisms – result in a difference of only one amino acid in the DNA sequence. These genetic variations are associated with variable responses to other mood-altering drugs, particularly six FDA-approved antipsychotics. (Roth was also one of the authors of the 2005 study examining these varied responses.)

Since LSD, psilocybin, DMT, and mescaline are known to interact with the same receptor, Roth and colleagues hypothesize that these slight but common genetic variations may play a role in the affinity of these substances. for a 5-HT2A receptor.

What did they do- Roth and his colleagues had previously developed technology that allowed them to assess the receptor’s ability to interact with these proteins. “Then we just applied that technology to that particular problem,” he says. “It’s just a way to accurately quantify the ability of receptors to interact with transducing proteins after a drug has bound to them.”

Cells expressing the different variations of the 5-HT2A receptor were cultured in a Petri dish. The researchers then applied the four different psychedelics to the cells. Using a biofluorescence technique, the researchers were able to follow the activity within the cell following the application of one of the four substances.

The researchers also looked at the activity of β-arrestin (βArr) proteins, which are also involved in regulation and signaling outcomes. For example, previous research suggests that when researchers eliminate β-arrestin proteins in mice, the mice have a significantly reduced response to LSD. The researchers followed the in vitro response at 5 minutes, 30 minutes, 1 hour, 2 hours and 3 hours after administration of the different psychedelics. As a control, the researchers used the wild-type 5-HT2A receptor (that is, without genetic variations).

The researchers found that the genetic variations affected how the receptor interacted with the drug.Getty

In particular, all the experiments of the study were made in vitro, that is, out of the body. The study did not investigate how genetic variations alter the potential therapeutic effects of the four different drugs. “That would be another study entirely,” Roth says. However, it yielded some interesting results that suggest these genetic differences might play a role in how someone reacts to different psychedelic compounds.

What they found— The researchers found that the genetic variations affected how the receptor interacted with the drug. For example, one of the variations had a reduced response to psilocin, a metabolite of psilocybin. A different genetic variation had a diminished response to two of the psychedelic compounds tested. Notably, none of the genetic variations responded to the compounds in the same way as the wild type. Moreover, no single genetic variation had the same effect on all psychedelics.

What this means for the future— While the researchers can’t say for sure what this means for psychedelic therapy, Roth says he hopes their data will be used by clinical researchers to retrospectively compare a patient’s response to one of these compounds. with their individual genetic variations.

“I suspect [the genetic vaariations] will have some effect,” he says. “Some of the differences here are quite significant. So it would be surprising if this didn’t somehow translate to an effect.

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